Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Baroreflex Sensitivity Modulates Vasodepressor Response to Nitroprusside ALEXANDER M. M. SHEPHERD, M.D., JOHN L. M C N A Y , M.D., P H . D . , MIN-SHUNG LIN, M.D., GARY E. MUSGRAVE, P H . D . , AND T. KENT KEETON, P H . D . Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017 SUMMARY Baroreflex activity is a determinant of the homeostatic response to alteration in blood pressure. We examined the factors that determine the magnitude of the vasodepressor response to sequential incremental intravenous infusions of sodium nitroprusside (NP), 0.05 to 6.4 yug/kg/min, in eight male patients with essential hypertension. Each infusion level was of 10 minutes' duration. Change from control values of mean arterial pressure (AMAP), heart rate (AHR) and plasma norepinephrine (ANE) were obtained at the end of each infusion level. Significant correlations were found between AMAP vs log dose NP, AHR vs AMAP and ANE vs AMAP for each patient (p < 0.05). However, the slopes of these relationships varied widely between subjects and were significantly correlated with the control blood pressure of each patient. In addition, the sympathetic responsiveness, as measured by ANE vs AMAP, was inversely correlated with the degree of vasodepressor response seen. Thus, the magnitude of the vasodepressor response was determined by two major factors: 1) the predrug blood pressure, possibly reflecting altered vascular geometry with hypertension; 2) the degree of sympathetic response, which probably acts by mediating the degree of reflex alpha-adrenergic-mediated arteriolar vasoconstriction. (Hypertension 5: 79-85, 1983) KEY WORDS * plasma norepinephrine • hypertension T • heart rate • humans thetic efferent nerves to the heart, and cardiovascular stress causes alteration in both vagal and sympathetic nerve activity.10"12 Accordingly, the use of changes in HR vs changes in blood pressure to measure BRS does not permit a separate examination of these two neural components. Third, alteration in the sensitivity of the cardiac beta-adrenoceptors to norepinephrine (NE) may contribute to variations in the HR versus blood pressure relationship. Finally, only the cardiac effects of alteration in sympathetic nerve activity are measured; therefore, those factors influencing the noradrenergic control of the resistance vessels are not included in this measure of BRS. Since peripheral vascular tone is affected by the sympathetic but not the parasympathetic nervous system, the neural regulation of vascular tone might be better reflected by plasma NE levels. HE level of baroreceptor activity, acting by way of the sympathetic nervous system, is a major determinant of the homeostatic response to perturbation of blood pressure. Changes in sensitivity of the baroreflex arc occur in hypertension,1"5 sleep,6 and with a g i n g . 2 3 5 Baroreflex sensitivity (BRS) is usually expressed in terms of the change in heart rate (HR), or R-R interval, for each unit of change in blood pressure.' 2 7~9 However, there are practical and theoretical limitations to this approach. First, in subjects receiving beta-adrenoceptor antagonists, the relationship between HR response and the level of sympathetic activity may change. Second, HR is controlled by a balance between the level of activity of the vagal and the sympa- Plasma NE concentration is considered to be a useful quantitative measure of the level of activity of the sympathetic nervous system, particularly during cardiovascular stress produced by isometric7' 'Oi 13 or dynamic14"16 exercise, tilt,17 change from recumbency to upright posture,7' "•18 exposure to cold,7'16- "• M induction of hypoglycemia,21 the Valsalva maneuver,16 and sodium balance.16> u-n From the Division of Clinical Pharmacology, Departments of Pharmacology and Medicine, The University of Texas Health Science Center, Audie Murphy Veterans Administration Hospital, San Antonio, Texas. Address for reprints: Alexander M.M. Shepherd, M.D., Ph.D., Departments of Pharmacology and Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284. Received May 26, 1982; revision accepted July 16, 1982. 79 80 HYPERTENSION To circumvent the limitations associated with using change in HR as an index of BRS, we used changes in the plasma concentration of NE to gauge the sympathetic component of the BRS in supine hypertensive patients. In addition, we measured the correlation between the level of sympathetic responsiveness as measured by plasma NE increments and the magnitude of the vasodepressor response seen after administration of sodium nitroprusside (NP). The baroreflex arc was activated by sequential stepwise reductions in blood pressure produced by incremental intravenous infusion rates of NP. This method provides a graded series of measurable stimuli for baroreflex activation. At each level of blood pressure reduction, HR and plasma NE and epinephrine (EP) concentrations were measured and compared with control values. Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017 Methods Eight patients (aged 45-55 years, weighing 85-116 kg) with essential hypertension were studied in hospital. All patients were receiving long-term therapy for their hypertension but antihypertensive medications except hydrochlorothiazide were stopped at least 6 days prior to the study. The patients were hospitalized for at least 4 days at bed rest to permit stabilization of blood pressure. Their hospital diet contained 137 mEq of sodium per day. Electrolyte balance was not quantitated; however, no consistent change of body weight was noted. The patients received nothing by mouth except water, beginning the previous midnight. The patients remained recumbent in bed without smoking throughout the study period. At 7 a.m., a pediatric scalp vein needle was placed in a forearm vein for blood sampling. A 5% solution of dextrose and water (D5W) was slowly infused through a second intravenous needle in the other arm which was used for NP infusion. Starting at 9 a.m., each patient was given serial incremental infusions of NP, each of 10 minutes' duration, by variable speed Harvard infusion pump into the side arm of the D5W infusion run at 0.5 irnVmin. Total fluid volume given was less than 50 ml over the 80-minute study. The NP infusion rate was increased over the range of 0.05-6.4 pig/kg/min, or until diastolic pressure was reduced to the level observed during the outpatient drug treatment of each individual patient. Blood pressure (Arteriosonde) and HR (EKG) were measured every 10 minutes for 2 hours before starting the NP infusion and every 2 minutes during the infusion period. The HR was counted over at least 30 seconds for each determination. Venous blood was drawn through the scalp vein needle during the last 2 minutes of the control period and during the 9th minute of each infusion period. The scalp vein needle was kept patent with 0.15 M saline containing 10 units heparin /ml. Samples were drawn into 5 ml plastic syringes and immediately transferred to precooled tubes containing EGTA (60 fig/ml) and reduced gluthathione (90 fig/ml). Plasma was separated at 4°C and stored at - 70°C until analyzed for NE and EP by a single isotope radioenzymatic assay.24 VOL 5, No 1, JANUARY-FEBRUARY 1983 Data Analysis Blood pressure values are expressed as mean arterial pressure (MAP) calculated as diastolic pressure plus one-third of pulse pressure. Analysis of variance indicated no significant variation in MAP during the 2 hours prior to NP infusion. Control MAP (CMAP) is expressed as the average of the 12 values obtained at 10-minute intervals prior to the infusion of NP. A change in MAP (AMAP) was taken to be the difference between CMAP and the average of the last three blood pressure values recorded during each infusion period. Control HR and the change in HR (AHR) were obtained at the same time intervals. Plasma NE and EP concentrations were the means of duplicate determinations. Changes in plasma NE (ANE) and EP (AEP) were the differences between the control values and the values obtained in the ninth minute of each infusion period. Baroreflex sensitivity was calculated as the ratio of AHR to AMAP, similar to the steady-state method, which has been shown to be equally reliable with the ramp method.3 Statistical analysis was performed by the methods specified in the text. These methods included one-way analysis of variance, least squares linear regression analysis, multiple linear stepwise regression analysis and Z transformation of the correlation coefficient, r. Statistical significance was taken to be p < 0.05. Catecholamine Assay This assay technique has previously been described in detail.24 Briefly, 100 fiL of plasma was added to a solution containing buffer, catechol-O-methyltransferase and 3H-S-adenosylmethionine. After the stoichiometric transfer of 3H-methyl groups to the catecholamine by catechol-O-methyltransferase (incubation at 37°C for 60 minutes), the 3H-O-methylated metabolites of NE and EP were separated by a rapid thin layer chromatographic procedure. This isolation procedure prior to counting the 3H-O-methylated metabolites permits a high degree of specificity in the differential assay of NE and EP. The intraassay and interassay coefficients of variation are 6% and 11% respectively, for both NE and EP. The limit of detection is 20 pg/ml for both compounds. Results By using infusion rates of NP ranging from 0.05 to 6.4 /xg/kg-min, an average of six (range, five to nine) stepwise decrements in MAP were elicited in each patient. The maximal reduction in MAP at the highest rate of infusion averaged 25 mm Hg and ranged from 14 mm Hg in the least hypertensive patient to 40 mm Hg in the most hypertensive patient. Linear regression analysis of data obtained from each patient revealed a significant log dose-response relationship between AMAP and the log of the infusion rate of NP (p g 0.005; fig. 1). The maximal rise in HR during NP-induced vasodepression averaged 26 beats/min (range, 18-38 beats/ min). Within each subject, a significant positive corre- 81 CATECHOLAMINE RESPONSE TO NITROPRUSSIDE/Shepherd et al. 40- I r-098 I 1 r-092 30X E E Q. r-096 A 1 / r-09e 20l/jf 10- //yCr r-099 r-093 00.01 0 0 5 O.KD Q20 0 4 0 1.00 2JD0 4.00 8 0 0 Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017 NP Infusion Rate (ng/kg/min) FIGURE 1. Individual plots of the best-fit calculated regression lines relating the logarithm of the infusion rate of sodium nitroprusside (NP) to the vasodepressor response seen. lation (p ^ 0.01) existed between the decrease in MAP and the resulting increase in HR (fig. 2 a). The mean plasma NE concentration prior to the administration of NP was 199 pg/ml (range, 162-435 pg/ ml). No relationship was found between the severity of the hypertension and the baseline levels of either NE (r = 0.5503) or EP (r = -0.1550) in the plasma. The stepwise decrements in MAP caused by increasing doses of NP were accompanied by stepwise increments in plasma NE concentration in all subjects (fig. 2 b). Moreover, a correlation existed between the rise in plasma NE concentration and the corresponding increase in HR at each infusion rate of NP in each patient (fig. 3). In only one subject was a significant correlation found between rise in EP and AMAP. The maximum rise in plasma EP was small (33 ± 6 pg/ml, mean ± SEM) compared with that of NE (275 ± 84 pg/ml). Although correlations were noted between AMAP/ log dose NP, AHR/AMAP, ANE7AMAP and AHR/ ANE within the data of each patient, a considerable amount of interindividual variation was found in the slopes of these relationships. For example, in some patients a small fall in MAP was associated with a (a) 300- FIGURE 2. Individual plots of the best-fit calculated regression lines relating the vasodepressor response seen to (a) the rise in heart rate (HR) and (b) the rise in plasma norepinephrine (NE) concentration. -= 200- 40- a. or x LZJ 20- 100- 20 40 20 0 40 AMAP(mmHg) 40-, FIGURE 3. Individual plots of the best-fit calculated regression lines relating the rise in plasma norepinephrine (NE) concentration to the rise in heart rate (HR). E a. .a cr 20- 100 200 ANE (pg/ml) 300 400 82 HYPERTENSION large increase in plasma NE concentration, whereas in other patients, a large decrease in MAP was accompanied by only a small rise in plasma NE levels. The slopes of the best-fit regression lines for each subject are shown in table 1. To determine whether CMAP was related to the slopes of these relationships, the slopes of the best-fit regression lines of each of these relationships were correlated against CMAP for each patient. This method of analysis revealed a positive correlation between CMAP and the slope of AMAP/log10 NP dose (fig. 4 a): AMAP/log10 NP dose = - 5 6 . 0 + 0.67 CMAP, where r = 0.8913, p = 0.0014. A negative correlation was noted between CMAP and the slopes of both AHR/AMAP (fig. 4 b) and ANE/ AMAP (fig. 4 c): VOL 5, No 1, JANUARY-FEBRUARY 1983 TABLE 1. CMAP and the Slopes of the Relationships Between the Measured Parameters Subject 1 2 3 4 5 6 7 8 AMAP/ CMAP log io (mm Hg) NPdose 98 10.0 107 17.8 108 15.3 15.5 109 13.2 113 37.4 123 131 23.5 46.4 152 AHR/ AMAP 1.85 1.36 1.57 1.40 1.30 0.33 1.20 0.41 ANE/ AMAP AHR/ ANE 18.6 14.0 30.5 12.1 9.4 0.087 0.070 0.055 0.107 0.080 0.081 0.087 0.140 4.3 13.3 2.37 CMAP = control mean arterial pressure; AMAP = change in mean arterial pressure from control; NP = nitroprusside; AHR = change in heart rate; ANE = change in plasma norepinephrine. Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017 AHR/AMAP = 4.1 - 0.03 CMAP, where r = 0.8052, p = 0.0128. ANE/AMAP = 51.1 - 0.32 CMAP, where r = 0.6347, p = 0.0935. Last, a positive correlation existed between CMAP and the slope of the AHR/ANE relationships (fig. 4 d): AHR/ANE = - 0 . 0 3 3 + 0.001 CMAP, where r = 0.6925, p = 0.0565. 60-, 80 The last two relationships failed to reach statistical significance. To determine whether the slopes of the individual dose response relationships were influenced by BRS or by the reactivity of the sympathetic nervous system, the slopes of the dose response curves were regressed against AHR/AMAP (fig. 5 a) and against ANE/ 3.0-1, 160 80 CMAP (mmHg) l60 120 160 FIGURE 4. Individual data, with calculated best-fit regression lines relating the baseline arterial blood pressure (CMAP) to the slopes of the relationships: (a) vasodepressor response vs logarithm of sodium nitroprusside (NP) infusion rate; (b) rise in heart rate (HR) vs vasodepressor response; (c) rise in plasma norepinephrine (NE) concentration vs vasodepressor response; (d) rise in HR vs rise in plasma NE concentration. CATECHOLAMINE RESPONSE TO NlTROPRUSSIDE/S/iep/imf et al. AMAP (fig. 5 b). The following regression equations were obtained: AMAP/logl0 AMAP/log10 NP dose where r = 0.9468, p AMAP/log10NP dose where r = 0.6870, p where r = 0.9714, p < 0.0001. = < = = 49.2 - 22.7 AHR/AMAP, 0.0001; 35.5 - 1.00 ANE/AMAP, 0.0590. Since the parameters CMAP, AHR/AMAP and ANE/ AMAP were likely to covary, multiple linear stepwise regression analysis was undertaken with AMAP/ log]0NP dose as the dependent variable and CMAP, AHR/AMAP, ANE/AMAP as independent variables. The following regression equation was obtained: NP dose = 8.57 + 0.27 - 15.64 AHR/AMAP, 83 CMAP This indicates that both CMAP and AHR/AMAP were independent determinants of the slope of the dose response curve. To determine if CMAP or BRS (expressed as AHR/ AMAP) was related to the extrapolated threshold values of the regression lines, AMAP vs log dose NP, AHR vs AMAP, and ANE vs AMAP, the threshold values were correlated against CMAP for each patient. No significant correlations could be found between CMAP and the relationships; AMAP vs log dose NP (p = 0.40); AHR vs AMAP (p = 0.60); ANE vs AMAP (p = 0.50). (a) Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017 40- 20- •a CO 10 o 20 30 AHR/AMAP 60-i (b) 40- 20- 10 20 30 ANE/AMAP FIGURE 5. Individual data, with calculated best-fit regression lines for the group, relating (a) the slope of the relationship A///?/AMAP and (b) the slope of the relationship ANE/AAMP, to the slope of the dose/response relationship (hMAPIlogio NP infusion rate). Discussion In the present study we have shown a positive correlation between slope of the NP vs blood pressure dose response curves and the predrug blood pressure. Similar relationships have been found for other vasodilators including diazoxide23 and minoxidil26 and for diuretics.27"29 We could not detect any interrelationship between the threshold dose of nitroprusside required and the baseline blood pressure. This supports the work of Sivertsson,30 who found no evidence of supersensitivity in the hand resistance vessels of hypertensive patients. Increased vascular sensitivity might be expected to be reflected in a shift of the threshold dose of vasodilator required to cause fall in pressure. Despite the potential limitations, already discussed, to using change in HR as a measure of baroreflex sensitivity, we were able to demonstrate good relationships between the slope of the dose-response relationship and both AHR/AMAP and baseline blood pressure. A relationship between baroreflex sensitivity and baseline blood pressure has been previously demonstrated.31 However, the relationship between baroreflex sensitivity and vasodepressor responsiveness has not been previously demonstrated. It indicates an association between this measure of baroreflex sensitivity and the degree of homeostatic responsiveness to reduction in blood pressure. The sympathetic nervous system is known to play an important role in the control of the circulation. However, it is difficult to assess the basal level of activity of the sympathetic nervous system in clinical studies. Although the plasma concentration of NE is generally regarded as a useful measurement of the level of stimulation of the sympathetic nervous system, the resting levels of plasma NE do not necessarily reflect sympathetic nervous system activity. This is probably in part due to the levels of NE in the blood, which are not determined solely by the rate of spillover from peripheral sympathetic nerves into the circulation. Additional factors influencing the plasma NE levels include variation in distribution and rate of metabolism, which 84 HYPERTENSION Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017 is seen in normal subjects,32 hypertensive patients, autonomic insufficiency, and following drug interventions.33 It may be for this reason that there is dispute as to the interrelationship between baseline plasma NE levels and the presence and extent of hypertension.22' 3K 34~36 However, plasma NE levels are considered to be representative of sympathetic nerve activity. ' 3 -" The failure of plasma EP to rise significantly indicates that adrenal medullary secretion is probably not a major source of the plasma catecholamines measured in this study. It is recognized that NP infusion results in increased plasma NE concentration.38 The slope of the relationship of ANE/AMAP may be regarded as reflecting the degree of stimulation of the sympathetic nervous system for each decrement in blood pressure induced by NP. As expected, therefore, the slope of ANE/AMAP was proportional to both baseline blood pressure (fig. 4 c) and the slope of the dose response curve (fig. 5 b). Multiple linear stepwise regression analysis indicated that control blood pressure and slope of the AHR/ AMAP relationship were independent correlates of the slope of the dose-response relationship. Accordingly, baseline blood pressure appeared to determine the slope of the dose-response relationship by an alternative or additional mechanism to its effect on baroreflex sensitivity. This additional mechanism may be the structural differences in vascular geometry caused by hypertension as demonstrated by Folkow.39 The dependence of the slope of the dose-response curve on the degree of tachycardia induced, rather than on the degree of sympathetic stimulation, may be because mechanisms other than sympathetic stimulation will contribute to the homeostatic response seen. Man in'T Veld et al.12 have shown that reduction of vagal tone is the principal mechanism for increase in HR and cardiac output seen when blood pressure is decreased with diazoxide. The degree of sympathetic stimulation will determine the reflexly mediated peripheral vasoconstriction that will oppose the vasodepression induced by NP. When Mancia et al.40 decreased transmural pressure in the carotid sinus by changing the pressure in a chamber placed around the neck, they found that peripheral vasoconstriction, presumably resulting from increased NE release and alpha-adrenoreceptor activation, was the only mechanism accounting for the pressor response. Thus, the mechanisms contributing to the homeostatic response seen following vasodilation may be complex and have not yet been fully elucidated. While our experiments do not rigorously define cause and effect, we propose that NE secretion relative to arterial pressure reduction provides an estimate of adrenergically mediated vasoconstriction. The latter effect would nonspecifically antagonize the vasodepressor effect of NP. Data from several animal studies support the conclusion that baroreflex activation of the sympathetic nervous system antagonizes the vasodepressor effect of NP. Flacke et al.41 have shown that the veratrum alkaloid, cryptenamine, which acts on baroreceptors, potentiates the vasodepressor effect of VOL 5, No 1, JANUARY-FEBRUARY 1983 NP. Greenway and Innes42 found that carotid reflex mechanisms reduced the vasodepressor response of anesthetized vagotomized cats to intravenous NP by approximately two-thirds. The principal mechanism of this physiological antagonism was defined as an increase in peripheral resistance. A reflex increase in iliac resistance during NP infusion in conscious dogs has been clearly demonstrated by Pagani et al.43 Accordingly, activation of vascular alpha-adrenoceptors may be a major mechanism by which autonomic reflexes modulate the vasodepressor response to vasodilator drugs. By contrast, the hemodynamic effects of altered autonomic control of heart rate and contractility may be relatively minor, since combined pretreatment with atropine and propranolol does not potentiate the vasodepressor response of supine hypertensive patients to intravenous bolus doses of diazoxide.12 In conclusion, we have demonstrated associations between the degree of vasodepressor response seen with graded infusions of NP and both the baroreflex sensitivity and baseline blood pressure. The latter association possibly reflects structural vascular changes related to the degree of hypertension. In addition, the data are consistent with the conclusion that adrenergically mediated vasoconstriction antagonizes the hypotensive response to nitroprusside in supine hypertensive patients. References 1. Bristow JD, Honour AJ, Pickering GW, Sleight P, Smyth HS: Diminished baroreflex sensitivity in high blood pressure. Circulation 39: 48, 1969 2. Gribbin B, Pickering TG, Sleight P, Peto R: Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res 29: 424, 1971 3. Randall O, Esler M, Culp B, Julio S, Zweiffer A: Determinants of baroreflex sensitivity in man. J L a b C l i n M e d 9 1 : 514, 1978 4. Komer PI: Role of cardiac output, volume and resistance factors in the pathogenesis of hypertension. Clin Sci 57 (suppl 5): 77s, 1979 5. Bertel O, Buhler FR, Kiowski W, Lutold BE: Decreased betaadrenoreceptor responsiveness as related to age, blood pressure, and plasma catecholamines in patients with essential hypertension. Hypertension 2: 130, 1980 6. Smyth HS, Sleight P, Pickering GW: Reflex regulation of arterial pressure during sleep in man. A quantitative method of assessing baroreflex sensitivity. Circ Res 24: 109, 1969 7. Palmer GJ, Ziegler MG, Lake CR: Response of norepinephrine and blood pressure to stress increases with age. J Gerontol 33: 482, 1978 8. Karemaker JM: Measurement of baroreflex sensitivity in hypertension research. In: Arterial Baroreceptors and Hypertension, edited by Sleight P. Oxford (Eng): Oxford Medical Publications, 1970, p 455 9. Farris IB, Iannos J, Jamieson GG, Ludbrook J: Comparison of methods for eliciting the baroreceptor-heart rate reflex in conscious rabbits. Clin Exp Pharmacol Physiol 7: 281, 1980 10. Martin CE, Shaver JA, Leon DF, Thompson ME, Reddy PS, Leonard JJ: Autonomic mechanisms in hemodynamic responses to isometric exercise. J Clin Invest 54: 104, 1974 11. Eckberg DL: Carotid baroreceptor stimulus-sinus node re- CATECHOLAMINE RESPONSE TO NYTROPRUSSIDE/Shepherd et al. 12. 13. 14. 15. 16. 17. Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017 18. 19. 20. 21. 22. 23. 24. 25. 26. sponse relationship in man. In Arterial Baroreceptors and Hypertension, edited by Sleight P. Oxford (Eng): Oxford Medical Publications, 1970, p 476 Man in'T Veld AJ, Wenting GJ, Boomsma F, Verhoeven RP, Schalekamp MADH: Sympathetic and parasympathetic components of reflex cardiostimulation during vasodilator treatment of hypertension. Br J Clin Pharmacol 9: 547, 1980 Lake CR, Ziegler MG, Kopin LI: Use of plasma norepinephrine for evaluation of sympathetic neuronal function in man. LifeSci 18: 1315, 1976 Haggendal J, Hartley LH, Saltin B: Arterial noradrenaline concentration during exercise in relation to the relative work levels. Scand J Clin Lab Invest 26: 337, 1970 Watson RDS, Hamilton CA, Reid JL, Littler WA: Changes in plasma norepinephrine, blood pressure and heart rate during physical activity in hypertensive man. Hypertension 1: 341, 1979 Robertson D, Johnson GA, Robertson RM, Nies AS, Shand EX3, Oates JA: Comparative assessment of stimuli that release neuronal and adrenomedullary catecholamines in man. Circulation 59: 637, 1979 Rosenthal T, Birch M, Osikowska B, Sever PS: Changes in plasma noradrenaline concentration following sympathetic stimulation by gradual tilting. Cardiovasc Res 12: 144, 1978 Cryer PE, Santiago JV, Shad S: Measurement of norepinephrine and epinephrine in small volumes in human plasma by single isotope derivative method: Response to upright posture. J Clin Endocrinol Metab 39: 1025, 1974 Winer N, Carter C: Effect of cold pressor stimulation on plasma norepinephrine, dopamine hydroxylase and renin activity. Life Sci 20: 887, 1977 Johnson DG, Hayward JS, Jacobs TP, Collis MD, Eckerson JD, Williams RH: Plasma norepinephrine responses of man in cold water. J Appl Physiol 43: 216, 1977 Santiago JV, Clarke WL, Shad SD, Cryer PE: Epinephrine, norepinephrine, glucagon, and growth hormone release in association with physiological decrements in the plasma glucose concentration in normal and diabetic man. J Clin Endocnnol Metab 51: 877, 1980 Henry DP, Luft FC, Weinberger MH, Fineberg NS, Grim CE: Norepinephrine in urine and plasma following provocative maneuvers in normal and hypertensive subjects. Hypertension 2: 20, 1980 Nicholls MG, Kiowski W, Zweifler AJ, Julius S, Schork MA, Greenhouse J: Plasma norepinephrine varies with dietary sodium intake. Hypertension 2: 29, 1980 Peuler JD, Johnson GA: Simultaneous single isotope radioenzymatic assay of plasma norepinephrine, epinephnne and dopamine. Life Sci 21: 625, 1977 Velasco M, Gallardo E, Plaja J, Guevara J, DeRojas E: A new technique for safe and effective control of hypertension with intravenous diazoxide. Curr Ther Res 19: 185, 1976 Shen D, O'Malley K, Gibaldi M, McNay JL: Pharmacodynamics of minoxidil as a guide for individualizing dosage regimens in hypertension. Clin Pharmacol Ther 17: 593, 1975 85 27. Cranston WI, Juel-Jensen BE, Semmence AM, Handfield Jones RPC, Forbes JA, Mutch LMM: Effects of oral diuretics on raised arterial pressure. Lancet 2: 966, 1963 28. Degnbol B, Dorph S, Mamer T: The effect of different diuretics on elevated blood pressure and serum potassium. Acta Med Scand 193: 407, 1973 29. Grieble HG, Johnston LC: Treatment of arterial hypertensive disease with diuretics. Arch Intern Med 110: 26, 1962 30. Sivertsson R: The hemodynamic importance of structural vascular changes in essential hypertension. Acta Physiol Scand (suppl) 343: 2, 1970 31. Floras JS, Hassan MO, Jones JV, Osikowska BA, Sever PS, Sleight P, Turner KL: Baroreceptor reflexes and the control of blood pressure and plasma noradrenaline in hypertension. IN Arterial Baroreceptors and Hypertension, edited by Sleight P. Oxford (Eng): Oxford Medical Publications, 1970, p 471 32. Fitzgerald GA, Hossmann V, Hamilton CA, Reid JL, Davies DS, Dollery CT: Interindividual variation in kinetics of infused norepinephrine. Clin Pharmacol Ther 26: 669, 1979 33. Esler M, Leonard P, Jackman G, Bobik A, Skews H: Study of noradrenaline uptake and spillover to plasma in normal subjects and patients with essential hypertension. Prog Biochem Pharmacol 17: 75, 1980 34. Louis WJ, Doyle AE, Anavekar SN: Plasma noradrenaline concentration and blood pressure in essential hypertension, pheochromocytoma and depression. Clin Sci Mol Med 48: 239s, 1975 35. Engelman K, Portnoy B, Sjoerdsma A: Plasma catecholamine concentrations in patients with hypertension. Circ Res 27 (suppl): 1141, 1970 36. De Champlain J, Farley L, Cousineau D, Van Ameringen MR: Circulating catecholamine levels in human and experimental hypertension. Circ Res 38: 109, 1976 37. Shepherd AMM, Lin M-S, Keeton TK, McNay JL: Plasma noradrenaline as a measure of baroreflex sensitivity in hypertensive man. Clin Sci 61: 165s, 1981 38. Dean CR, Maling T, Dargie HJ, Reid JL, Dollery CT: Effect of propranolol on plasma norepinephrine during sodium nitroprusside-induced hypotension. Clin Pharmacol Ther 27: 156, 1980 39. Folkow B: Relationship between physical vascular properties and smooth muscle function: Its importance for vascular control and reactivity. Clin Exp Pharmacol Physiol 2: 55, 1975 40. Mancia G, Ludbrook J, Ferrari A, Gregorina L, Zanchetti A: Baroreceptor reflexes in human hypertension. Circ Res 43: 170, 1978 41. Flacke JW, Flacke WE, Cant JW: Reflex responses to sodium nitroprusside and their control by cryptenamine. Anesth Analg 59: 909, 1980 42. Greenway CV, Innes IR: Effect of carotid sinus baroreceptor reflex on responses to phenylephrine and nitroprusside in anesthetized cats. J Cardiovasc Pharmacol 3: 169, 1981 43. Pagani M, Vatner SF, Braunwald E: Hemodynamic effects of intravenous sodium nitroprusside in the conscious dog. Circulation 57: 144, 1978 Baroreflex sensitivity modulates vasodepressor response to nitroprusside. A M Shepherd, M S Lin, J L McNay, G E Musgrave and T K Keeton Hypertension. 1983;5:79-85 doi: 10.1161/01.HYP.5.1.79 Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017 Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1983 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://hyper.ahajournals.org/content/5/1/79 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Hypertension is online at: http://hyper.ahajournals.org//subscriptions/