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Abnormalaties of carbohydrate metabolism may play a role in the etiology and clinical course of hypertension
TIPS
78
'~.~,i i ~ ~
"
--]LLL]~-F~~F:,C-FT]E-iZ__E]
Abnorma ties of carbohydrate metabolism may play a role in the etiology and clinical course of hypertension blood pressure was associated Drug therapy of hypertension has With resistance to insulinbeen shown to prevent stroke, stimulated glucose uptake, and congestive heart failure and renal this defect has now been docufailure. However, the observation mented in patients with untreated that risk of myocardial infarction hypertension 1~'12. Furthermore, does not appear to be reduced insulin resistance and hyperby treatm2nt of .hypertension insulinemia have been noted to remains puzzling l"a. This issue is occur in spontaneously hypertenone of the major unsolved probsive rats is. Finally, blood pressure lems in hypertension research. elevation can be seen within two Concern has focused on the posweeks when normal Spraguesibility that this failure to reduce Dawley rats are fed a fructoserisk of coronary artery disease enriched diet ~4. Rats treated in this may be in part due to abnormalfashion also become insulin resisities of lipoprotein metabolism tant, hyperinsulinemic, and hyperassociated with the use of certain triglyceridemic ~4, indicating that anti-h:-cpertensive drugs 4'5. Howabnormalities of lipid metabolism ever, ~t is now apparent that accompany the changes in carbochanges in plasma lipoprotein hydrate metabolism in this form of concentration exist in untreated patients with hypertension which experimental hypertension. Demonstration that insulin" can increase their risk of coronary resistance and hyperinsulinemia artery disease s,6. More recently it are associated with high blood has been shown that abnormalpressure in both human beings ities of carbohydrate metabolism and rats with experimental hyperalso eT,ist in untreated patients tension permits the speculation with h~gh blood pressure 7-1°, and that these changes in insulin these changes may play a role in metabolism play a role in the both the etiology and the clinical development of hypertension. course of hyi~ertension and assoSpecifically, acute hyperinsulindated abnom~alities of lipoproemia has been shown to increase tein metabolism. Although it has been known for Na + transport across the toad some time that plasma glucose bladder TM, stimulate volume reabconcentrations in response to an sorption by the rat proximal conoral glucose load are higher in voluted tubule 16, and reduce Na + patients with high blood pressure excretion in human beings 17. In than in a control population TM,the addition, acute hyperinsulinemia potential importance of abnormal has been noted to increase plasma carbohydrate metabolism in the catecholamine concentration in syndrome of hypertension has control subjects TM. Thus, hyperinrecently received impetus from sulinemia, secondary to insulin observations that insulin metabolresistance, could increase blood ism is also abnormal in these pressure by modification of plaspatients 9-12. This was initially ma volume and/or sympathetic demonstrated by the observation activity. Moreover, it has been that plasma insulin concentration suggested that lowering of intrawas elevated in patients with cellular pH may be an important hypertension when compared feature of hypertension and that with an appropriately matched this change could be a consecontrol group of individuals with quence of insulin resistance ~9. normal blood pressure 9,1°. The fact Insulin resistance and hyperinthat both plasma glucose and su!inemia could also contribute to insulin concentrations were the increased risk of coronary higher than normal following a artery disease associated with glucose load suggested that high hypertension, both directly and ~) 1988,Elsevier Publications, Cambridge 016.~- 61471881502.00
-
March !988 [V~!. 9]
indirectly. Hyperinsulinemia has been identified as a primary risk factor for coronary artery disease in prospective studies 2°'21. In addition, increased levels of very low density lipoproteintriglyceride (VLDL-TG), and decreased levels of high density lipoprotein-cholesterol (HDLcholesterol) levels have been shown to be associated with hyperinsulinemia 22. It may be that both of these changes in lipoprotein metabolism are secondary to the insulin resistance and hyperinsulinemia. Since both a high VLDL-TG and a low HDLcholesterol have also been identified as risk factors for coronary artery diseai~ez~.z4, it could be ~ g u e d that several additional risk factors result from insulin resistance and hyperinsulinemia. At the least, it seems reasonable to suggest that multiple factors, including abnormalities of carbohydrate and lipid metabolism and hypertension, exist in certain individuals, giving them increased risk of developing coronary artery disease. Indeed, this clustering of risk factors for coronary' artery disease has recently been documented ~. Based upon the considerations described above, there are a number of possible reasons that treatment of hypertension has not resulted in a reduction in morbidity and mortality from coronary artery disease. Therapy has focused on pharmacological approaches to lowering blood pressure, with little attention paid to the associated underlying metabolic abnormalities. While emphasis has recently been given to the fact that anti-hypertensive drugs differ in their effects on lipoprotein metabolism, it does not appear that a great deal of attention has been paid to developing treatment programs that would alleviate the defects in carbohydrate and lipoprotein metabolism that seem to characterize patients with hypertension as a group. Indeed, the changes in glucose and insulin metabolism seem to have been largely ignored. D
[]
[]
We would suggest that therapeutic approaches to lower blood pressure should be monitored and modified if necessary, in order not
TIPS - M a r c h 1988 [V,,l.-. ~!
to accentuate the metabolic defects known to exist in patients with high blood pressure and which may predispose them to develop coronary artery disease. More importantly, efforts should be made to initiate treatment programs aimed at allew~ating the defects in carbohydrate and lipoprotein metabolism present in these patients. If this can be accomplished, lowering blood pressure may be shown to reduce the risk of coronary artery disease.
79 Agus, Z. 0976) j. Clin. Invest. 58, 83-90 17 Baum, M. (1987) J. Clin. Invest. 79,1104-1109 18 Rowe, J. W., Young, J.B., Minaker, K.L., Stevens, A.L., Pallotta, J. and Landsberg, L (1981) Diabetes 30, 219 19 Resnick, L. M., Gupta, R. K., Sosa, E., Corbett, M. L. and Laragh, ]. H. (1987) Proc. Natl Acad. Sci. USA 84, 7663.-7667 20 Pyorala, K. (1979) Diabetes Care 2, 131141 21 Ducimetiere, P., Eschwege, E., Papoz,
23 24 25
The making and shaking of memories
Throu_gh history, the relation between making and shaking has been complex. Some things are unmade by shaking, for example houses of cards, or certain Department of Medicine, Stanford University School of Medicine and Geriatric Research, superficial human relations. Education and Clinical Center, Veterans Others cannot be made without Administration Medical Center, Polo Alto, CA shaking, like mayonnaise and cer94304, USA. tain cocktails. Early practitioners of cognitive science, like grammar school teachers and parents of the References Belle Epoque, believed that shakVeterans Administration Cooperative ing was important in order to Study Group on Antihypertensive Agents (1970) J. Am. Med. Assoc. 213, make memories: they used to grab 1143-1152 their subjects by both arms, shake 2 Management Committee of the Austrathem and yell, 'Now see if you can lian Therapeutic Trial in Mild Hyperget this straight!' tension (1982) Lancet i, 185--191 3 Multiple Risk Factor Intervention Trial More recent research, conResearch Group (1982) J. Am. Med. ducted in laboratory animals, sugAssoc. 24'8, 1465-1477 gested a different, in fact opposite, 4 Weinberger, M. H. (1986) Am. ]. Med. relation between shaking and the 83, 64-70 making of memories. Convulsant 5 MacMahon, S. W., MacDonald, G.I. and Blacket, R. B. (1985) Arteriosclerosis treatments, like electroconvulsive 5, 391--396 shock (ECS) or pentetrazole, make 6 Shieh, S-M., Shen, M., Fuh, M. M-T., animals shake. When given Chen, Y-D. I. and Reaven~ G. M. (1987) shortly after training, these treatArteriosclerosis 67, 49-55 ments cause amnesia. Until 7 Stamler, J., Rhomberg, P., Schoenberger, J.A., Shekelle, R.B., Dyer, A., recently, this was attributed to an ShekeUe, S., Stamler, R. and Wannainterference with the making of maker, J. (1975) ]. Chronic Dis. 28, 527memories1: the effect of the con548 vulsant treatments was thought to 8 Jarrett, R. J.~ Keen, H., McCartney, M., Fuller, J.H., Hamilton, P.J.S., Reid, be essentially irreversible. Three D.D. and Rose, G. (1!978) Int. ]. papers published between August Epidemiol. 15-24 and September 1987 suggest a dif9 Lucas, C. P., Estigarribia,I. A., Darga, ferent interpretation. L.L. and Reaven, G. M. (1985) Hyper. Netto et ai. 2 trained different tension 7, 702-706 10 Modan, M., Halkin, H., Almog, S., groups of rats in three behavioral Lusky, A., Eshkil, A., ~hefi, M., Shitrit, tasks: step-down inhibitory A. and Fuchs, A. (1985) ]. Clin. Invest. avoidance, shuttle avoidance, and 75, 809-817 habituation o~ rearing in an open 11 Ferrannini, E., Buzzigoli, G., Bonadona, R., Giorico, M.A., Oleggini, M., Grafield. In all three tasks, immediate ziadei, L., Pedrineili, R., Grandi, L. and post-training 'ECS disrupted Bevilacqua, S, (1987) N. F,ngl. J. Med. retention, as measureJ in a test 317, 350-357 session carried out 24 h later. The 12 Shen, D-C., Shieh, S-M., Fuh, M. M-T., disruption was cancelled by a Wu, D-A., Chen, Y-D. I. and Reaven,, G.M. I. Clin. Endocrinol. Metab. (in second ECS, or by an i.v. injection press) of the opioid peptide [~:endorphin 13 Mondon, C. E. and Reaven, G. M. Meta(2.0 pg kg-I) 5 min prior to the test bolism (in press) session. 14 Hwang, S-S., Ho, H., Hofhnan, I?,.B. and Reaven, G. M. (.1987)Hyperter~.sion Baratti 3 trained mice in a step10, 512--516 through inhibitory avoidance 15 Andres,R. and Crabbe,J. (1966;PhysioL paradigm and made them amnesic Biochtm. 74, 538-540 by a post-training i.p. injection of 16 DeFronzo, R. A., Goldberg, M. and GERALD M. REAVEN AND BRIAN B. HOFFMAN
22
L., Richard, J. L., Claude, J. R. and Rosselin, G. (1980) Diabetologia 19, 205-210 Stalder, M., Pometta, D. and Suenram, A. (1981) DiatJewlc;~,;:,21, 544-5~8 Miller, G. J. and Miller, N. rE: (~q75) Lancet i, 16--19 Carlson, L. A., Bottiger, L.E. and Ahfeldt, P. E. (1979) Acta. Med. Scand. 206, 351-360 Zava.-oni, I.,D~Jl'Aglio, E., Bonora, E., AIpi, O., Passe.% M. and Reaven, G. M. (1987) Am. J. M~d. 83, 609--612
pentetrazole (~.5.0mg kg-~). The effect of pentetrazole was reversed either by the post-training i.p. administration of naltrexone (0.01 or 0.1 mg kg-1) - as had, indeed, been previously described for the effect of ECS (see Refs 2 and 3) - or by the pre-test i.p. administration of 15-endorphin (0.1 pg kg-~;). The effect of naltrexone was not shared by its peripherally-active Nmethyl bromide derivative, or by the K-receptor antagonist MR2266 (both in doses from 0.01 to 10.0 mg kg-1). Spanis and Squire 4 studied the effect of a series of ECSs on a stepthrough inhibitory avoidance response in mice. Four ECSs were given I h apart, 1-180 d after training, and retention of the response was measured 7 d, 14 d, or 28 d after the ECSs. The ECS series caused temporally graded amnesia (retention scores were lower when the task was ~cquired shortly before the treatment) but there was some degree of spontaneous recovery of floe amnesia for memories acquire~i 7 d or more (but not 5 d or less) prior to the ECSs. The data on the recovery of ECS amnesia by pre-test 13-endorphin, or by a pre-test ECSz are in the same class with others showing similar recoveries following a pretest administration of vasopressin s, cholecytokynin 6, or melanotropin 7. Both the date, on the recovery of ECS amne.~,ia by ~-endorphin 2 and those on the r~cove~y of pentetrazole amnesia by po~,t-training nal~,exone or pretest O-endorphin admir~istration 3 hav~ been explained by their a ~ o r s by the previous finding t~/at ECS and pentetrazole release a =hassiw amount of brain opioids; ~-endorphin and other brain opioids, acting at the post-training period, induce s~ate dependency (see Refs 2 and ~).
O 1988,BlJevierPublications, Cambrldp 016S- 6147/88/$02,00
78
'~.~,i i ~ ~
"
--]LLL]~-F~~F:,C-FT]E-iZ__E]
Abnorma ties of carbohydrate metabolism may play a role in the etiology and clinical course of hypertension blood pressure was associated Drug therapy of hypertension has With resistance to insulinbeen shown to prevent stroke, stimulated glucose uptake, and congestive heart failure and renal this defect has now been docufailure. However, the observation mented in patients with untreated that risk of myocardial infarction hypertension 1~'12. Furthermore, does not appear to be reduced insulin resistance and hyperby treatm2nt of .hypertension insulinemia have been noted to remains puzzling l"a. This issue is occur in spontaneously hypertenone of the major unsolved probsive rats is. Finally, blood pressure lems in hypertension research. elevation can be seen within two Concern has focused on the posweeks when normal Spraguesibility that this failure to reduce Dawley rats are fed a fructoserisk of coronary artery disease enriched diet ~4. Rats treated in this may be in part due to abnormalfashion also become insulin resisities of lipoprotein metabolism tant, hyperinsulinemic, and hyperassociated with the use of certain triglyceridemic ~4, indicating that anti-h:-cpertensive drugs 4'5. Howabnormalities of lipid metabolism ever, ~t is now apparent that accompany the changes in carbochanges in plasma lipoprotein hydrate metabolism in this form of concentration exist in untreated patients with hypertension which experimental hypertension. Demonstration that insulin" can increase their risk of coronary resistance and hyperinsulinemia artery disease s,6. More recently it are associated with high blood has been shown that abnormalpressure in both human beings ities of carbohydrate metabolism and rats with experimental hyperalso eT,ist in untreated patients tension permits the speculation with h~gh blood pressure 7-1°, and that these changes in insulin these changes may play a role in metabolism play a role in the both the etiology and the clinical development of hypertension. course of hyi~ertension and assoSpecifically, acute hyperinsulindated abnom~alities of lipoproemia has been shown to increase tein metabolism. Although it has been known for Na + transport across the toad some time that plasma glucose bladder TM, stimulate volume reabconcentrations in response to an sorption by the rat proximal conoral glucose load are higher in voluted tubule 16, and reduce Na + patients with high blood pressure excretion in human beings 17. In than in a control population TM,the addition, acute hyperinsulinemia potential importance of abnormal has been noted to increase plasma carbohydrate metabolism in the catecholamine concentration in syndrome of hypertension has control subjects TM. Thus, hyperinrecently received impetus from sulinemia, secondary to insulin observations that insulin metabolresistance, could increase blood ism is also abnormal in these pressure by modification of plaspatients 9-12. This was initially ma volume and/or sympathetic demonstrated by the observation activity. Moreover, it has been that plasma insulin concentration suggested that lowering of intrawas elevated in patients with cellular pH may be an important hypertension when compared feature of hypertension and that with an appropriately matched this change could be a consecontrol group of individuals with quence of insulin resistance ~9. normal blood pressure 9,1°. The fact Insulin resistance and hyperinthat both plasma glucose and su!inemia could also contribute to insulin concentrations were the increased risk of coronary higher than normal following a artery disease associated with glucose load suggested that high hypertension, both directly and ~) 1988,Elsevier Publications, Cambridge 016.~- 61471881502.00
-
March !988 [V~!. 9]
indirectly. Hyperinsulinemia has been identified as a primary risk factor for coronary artery disease in prospective studies 2°'21. In addition, increased levels of very low density lipoproteintriglyceride (VLDL-TG), and decreased levels of high density lipoprotein-cholesterol (HDLcholesterol) levels have been shown to be associated with hyperinsulinemia 22. It may be that both of these changes in lipoprotein metabolism are secondary to the insulin resistance and hyperinsulinemia. Since both a high VLDL-TG and a low HDLcholesterol have also been identified as risk factors for coronary artery diseai~ez~.z4, it could be ~ g u e d that several additional risk factors result from insulin resistance and hyperinsulinemia. At the least, it seems reasonable to suggest that multiple factors, including abnormalities of carbohydrate and lipid metabolism and hypertension, exist in certain individuals, giving them increased risk of developing coronary artery disease. Indeed, this clustering of risk factors for coronary' artery disease has recently been documented ~. Based upon the considerations described above, there are a number of possible reasons that treatment of hypertension has not resulted in a reduction in morbidity and mortality from coronary artery disease. Therapy has focused on pharmacological approaches to lowering blood pressure, with little attention paid to the associated underlying metabolic abnormalities. While emphasis has recently been given to the fact that anti-hypertensive drugs differ in their effects on lipoprotein metabolism, it does not appear that a great deal of attention has been paid to developing treatment programs that would alleviate the defects in carbohydrate and lipoprotein metabolism that seem to characterize patients with hypertension as a group. Indeed, the changes in glucose and insulin metabolism seem to have been largely ignored. D
[]
[]
We would suggest that therapeutic approaches to lower blood pressure should be monitored and modified if necessary, in order not
TIPS - M a r c h 1988 [V,,l.-. ~!
to accentuate the metabolic defects known to exist in patients with high blood pressure and which may predispose them to develop coronary artery disease. More importantly, efforts should be made to initiate treatment programs aimed at allew~ating the defects in carbohydrate and lipoprotein metabolism present in these patients. If this can be accomplished, lowering blood pressure may be shown to reduce the risk of coronary artery disease.
79 Agus, Z. 0976) j. Clin. Invest. 58, 83-90 17 Baum, M. (1987) J. Clin. Invest. 79,1104-1109 18 Rowe, J. W., Young, J.B., Minaker, K.L., Stevens, A.L., Pallotta, J. and Landsberg, L (1981) Diabetes 30, 219 19 Resnick, L. M., Gupta, R. K., Sosa, E., Corbett, M. L. and Laragh, ]. H. (1987) Proc. Natl Acad. Sci. USA 84, 7663.-7667 20 Pyorala, K. (1979) Diabetes Care 2, 131141 21 Ducimetiere, P., Eschwege, E., Papoz,
23 24 25
The making and shaking of memories
Throu_gh history, the relation between making and shaking has been complex. Some things are unmade by shaking, for example houses of cards, or certain Department of Medicine, Stanford University School of Medicine and Geriatric Research, superficial human relations. Education and Clinical Center, Veterans Others cannot be made without Administration Medical Center, Polo Alto, CA shaking, like mayonnaise and cer94304, USA. tain cocktails. Early practitioners of cognitive science, like grammar school teachers and parents of the References Belle Epoque, believed that shakVeterans Administration Cooperative ing was important in order to Study Group on Antihypertensive Agents (1970) J. Am. Med. Assoc. 213, make memories: they used to grab 1143-1152 their subjects by both arms, shake 2 Management Committee of the Austrathem and yell, 'Now see if you can lian Therapeutic Trial in Mild Hyperget this straight!' tension (1982) Lancet i, 185--191 3 Multiple Risk Factor Intervention Trial More recent research, conResearch Group (1982) J. Am. Med. ducted in laboratory animals, sugAssoc. 24'8, 1465-1477 gested a different, in fact opposite, 4 Weinberger, M. H. (1986) Am. ]. Med. relation between shaking and the 83, 64-70 making of memories. Convulsant 5 MacMahon, S. W., MacDonald, G.I. and Blacket, R. B. (1985) Arteriosclerosis treatments, like electroconvulsive 5, 391--396 shock (ECS) or pentetrazole, make 6 Shieh, S-M., Shen, M., Fuh, M. M-T., animals shake. When given Chen, Y-D. I. and Reaven~ G. M. (1987) shortly after training, these treatArteriosclerosis 67, 49-55 ments cause amnesia. Until 7 Stamler, J., Rhomberg, P., Schoenberger, J.A., Shekelle, R.B., Dyer, A., recently, this was attributed to an ShekeUe, S., Stamler, R. and Wannainterference with the making of maker, J. (1975) ]. Chronic Dis. 28, 527memories1: the effect of the con548 vulsant treatments was thought to 8 Jarrett, R. J.~ Keen, H., McCartney, M., Fuller, J.H., Hamilton, P.J.S., Reid, be essentially irreversible. Three D.D. and Rose, G. (1!978) Int. ]. papers published between August Epidemiol. 15-24 and September 1987 suggest a dif9 Lucas, C. P., Estigarribia,I. A., Darga, ferent interpretation. L.L. and Reaven, G. M. (1985) Hyper. Netto et ai. 2 trained different tension 7, 702-706 10 Modan, M., Halkin, H., Almog, S., groups of rats in three behavioral Lusky, A., Eshkil, A., ~hefi, M., Shitrit, tasks: step-down inhibitory A. and Fuchs, A. (1985) ]. Clin. Invest. avoidance, shuttle avoidance, and 75, 809-817 habituation o~ rearing in an open 11 Ferrannini, E., Buzzigoli, G., Bonadona, R., Giorico, M.A., Oleggini, M., Grafield. In all three tasks, immediate ziadei, L., Pedrineili, R., Grandi, L. and post-training 'ECS disrupted Bevilacqua, S, (1987) N. F,ngl. J. Med. retention, as measureJ in a test 317, 350-357 session carried out 24 h later. The 12 Shen, D-C., Shieh, S-M., Fuh, M. M-T., disruption was cancelled by a Wu, D-A., Chen, Y-D. I. and Reaven,, G.M. I. Clin. Endocrinol. Metab. (in second ECS, or by an i.v. injection press) of the opioid peptide [~:endorphin 13 Mondon, C. E. and Reaven, G. M. Meta(2.0 pg kg-I) 5 min prior to the test bolism (in press) session. 14 Hwang, S-S., Ho, H., Hofhnan, I?,.B. and Reaven, G. M. (.1987)Hyperter~.sion Baratti 3 trained mice in a step10, 512--516 through inhibitory avoidance 15 Andres,R. and Crabbe,J. (1966;PhysioL paradigm and made them amnesic Biochtm. 74, 538-540 by a post-training i.p. injection of 16 DeFronzo, R. A., Goldberg, M. and GERALD M. REAVEN AND BRIAN B. HOFFMAN
22
L., Richard, J. L., Claude, J. R. and Rosselin, G. (1980) Diabetologia 19, 205-210 Stalder, M., Pometta, D. and Suenram, A. (1981) DiatJewlc;~,;:,21, 544-5~8 Miller, G. J. and Miller, N. rE: (~q75) Lancet i, 16--19 Carlson, L. A., Bottiger, L.E. and Ahfeldt, P. E. (1979) Acta. Med. Scand. 206, 351-360 Zava.-oni, I.,D~Jl'Aglio, E., Bonora, E., AIpi, O., Passe.% M. and Reaven, G. M. (1987) Am. J. M~d. 83, 609--612
pentetrazole (~.5.0mg kg-~). The effect of pentetrazole was reversed either by the post-training i.p. administration of naltrexone (0.01 or 0.1 mg kg-1) - as had, indeed, been previously described for the effect of ECS (see Refs 2 and 3) - or by the pre-test i.p. administration of 15-endorphin (0.1 pg kg-~;). The effect of naltrexone was not shared by its peripherally-active Nmethyl bromide derivative, or by the K-receptor antagonist MR2266 (both in doses from 0.01 to 10.0 mg kg-1). Spanis and Squire 4 studied the effect of a series of ECSs on a stepthrough inhibitory avoidance response in mice. Four ECSs were given I h apart, 1-180 d after training, and retention of the response was measured 7 d, 14 d, or 28 d after the ECSs. The ECS series caused temporally graded amnesia (retention scores were lower when the task was ~cquired shortly before the treatment) but there was some degree of spontaneous recovery of floe amnesia for memories acquire~i 7 d or more (but not 5 d or less) prior to the ECSs. The data on the recovery of ECS amnesia by pre-test 13-endorphin, or by a pre-test ECSz are in the same class with others showing similar recoveries following a pretest administration of vasopressin s, cholecytokynin 6, or melanotropin 7. Both the date, on the recovery of ECS amne.~,ia by ~-endorphin 2 and those on the r~cove~y of pentetrazole amnesia by po~,t-training nal~,exone or pretest O-endorphin admir~istration 3 hav~ been explained by their a ~ o r s by the previous finding t~/at ECS and pentetrazole release a =hassiw amount of brain opioids; ~-endorphin and other brain opioids, acting at the post-training period, induce s~ate dependency (see Refs 2 and ~).
O 1988,BlJevierPublications, Cambrldp 016S- 6147/88/$02,00