Studies on the role of angiotensin in experimental renovascular hypertension: an immunologic approach.

The role of angiotensin in three forms of experimental hypertension was assessed in rats. First, the acute blood pressure response to injected angiotensin amide and angiotensin acid was determined. Rats made hypertensive with deoxycorticosterone and saline showed exaggerated responses; rats made hypertensive by clipping one renal artery showed depressed responses; and rats made hypertensive by clipping one renal artery and contralateral nephrectomy showed normal responsivity to angiotensin amide but depressed responsivity to angiotensin acid. These findings suggested that different mechanisms may be involved in the three types of hypertension studied. To assess the role of angiotensin in these hypertensive rats the blood pressure response, the presence of antibodies determined by radioimmune techniques, and the degree of refractoriness to injected angiotensin after immunization with angiotensin were studied. None of six rats made hypertensive by deoxycorticosterone and saline, and none of five mock immunized rats with renal hypertension of both types had a fall in blood pressure. By contrast, of the 20 rats with both types of renal hypertension in which antibody determinations were made, 11 had developed a significant antibody titer, of which seven showed a significant reduction in blood pressure at the time of antibody determination, and three of the remaining four had a significant blood pressure reduction earlier in their course. None of the nine renal hypertensive rats without demonstrable antibodies had a reduced blood pressure at the time of antibody determination, and only one had an earlier reduction in blood pressure. The renal hypertensive rats were all refractory to injected angiotensin after immunization. These results suggest a primary role for angiotensin in both forms of renal hypertension.

Renin-angiotensin-aldosterone system in diabetes mellitus.

The renin-angiotensin-aldosterone system appears to function normally in uncomplicated diabetes mellitus. Alterations in this system, however, have been observed in several of the microvascular and electrolyte complications associated with this disease. Plasma renin activity (PRA) and aldosterone are decreased in diabetic with nephropathy and hypertension, in those with neuropathy including orthostatic hypotension, and in those with hypoaldosteronism. PRA is low in rats with uncontrolled, nonketotic diabetes, and pressor responsiveness to angiotension II is increased in patients with diabetic retinopathy. Potential mechanisms responsible for the decreased PRA include plasma volume expansion, hyalin destruction of the juxtaglomerular cells, defective synthesis of renin, and inadequate catecholamine stimulation of renin, and inadequant cathecholamine stimulation of renin release. In diabetic ketoacidosis, PRA and aldosterone are stimulated secondary to the associated dehydration with hypovolemia. This report reviews the current status of the function of the renin-angiotensin-aldosterone system in diabetes mellitus and proposes a possible role for the altered function of this system in the pathophysiology of several diabetic complications.

Renin-angiotensin system in phlorhizin compared with alloxan diabetes in the rat.

In alloxan-treated diabetic rats, plasma renin activity (PRA) is decreased. One possible mechanism that may explain the decreased PRA is an increased delivery of sodium to the macula densa produced by the glucose osmotic diuresis, resulting in decreased renin release. To evaluate this possible mechanism, rats with phlorhizin diabetes, which produces a glucose osmotic diuresis without hyperglycemia, were studied and compared with rats with alloxan-induced diabetes. Whereas phlorhizin-treated rats had low blood glucose and alloxan-treated rats had elevated glucose, the glucose osmotic diuresis was similar in the two groups. PRA and plasma renin concentration (PRC) were significantly increased in the phlorhizin group. In the alloxan group, PRA was decreased and angiotensin II sensitivity increased, both significantly. Plasma renin substrate (PRS) remained adequate in each group. These results suggest that the decreased PRA in alloxan-induced diabetes is due neither to factors associated with the glucose osmotic diuresis including changes in renal tubular sodium not to decreased PRS.

Aldosterone responsiveness in patients with diabetes mellitus.

Plasma aldosterone (PA) and plasma renin activity (PRA) were determined in 44 diabetics, of whom nine were normotensive but not nephropathic (group 1), 10 were hypertensive but not nephropathic (group 2), and 25 were hypertensive and nephropathic (group 3); they were kept in balance on a diet composed of 10 to 20 mEq. of sodium (Na) and 100 mEq. of potassium (K). Supine PA in group 1 was 38 +/- 7 ng. per deciliter, whereas in normals it was 24 +/- 2 ng. per deciliter (P less than 0.05); beyond that, neither supine nor upright PA or PRA differed significantly from normal in groups 1 and 2. By contrast, in group 3, supine PA was 13 +/- 1 ng. per deciliter and PRA 2.0 +/- 0.2 ng./ml. and upright PA was 39 +/- 7 ng. per deciliter and PRA 3.8 +/- 0.5 ng./ml., all significantly lower than those in the other groups (P less than 0.01). Nine patients, one in group 1 and eight in group 3, had low supine and upright PA and PRA; four had hyperkalemia. An additional nine patients in group 3 had low upright PA, with normal or low PRA; two had hyperkalemia. Of the 18 patients with low upright PA, K correlated with glucose (R = 0.46, P less than 0.05). These results suggest (1) the renin-aldosterone system generally responds normally in diabetics without nephropathy but responds subnormally when nephropathy is present, (2) hyporeninemic hypoaldosteronism is frequent in diabetics with nephropathy but may occur in the absence of clinical nephropathy, and (3) hyperkalemia in some diabetic patients may be secondary to hypoaldosteronemia and hyperglycemia.

Plasma renin activity and hypertension in diabetes mellitus.

Plasma renin activity (PRA) was determined in 48 patients with diabetes mellitus in sodium balance on a 10-20 mEq. Na diet. Nine were normotensive (group I), 11 11 were hypertensive without diabetic nephropathy (group III). Results were compared with those in 16 normal subjects and 49 nondiabetic patients with essential hypertension in similar Na balance. Mean supine PRA did not differ significantly among groups I and II, normal subjects, and patients with essential hypertension. Group III diabetics had a supine PRA of 2.4 +/- 0.4 ng./ml./hr. (x +/- S.E.M.), significantly lower than the other diabetic groups (P less than 0.005) and normal subjects (P less than 0.05). Upright PRA was 12.8 +/- 2.2 in group I diabetics, similar to that in normal subjects (13.3 +/- 2.3), and 8.1 +/- 1.4 in group II diabetics, similar to that in essential hypertensives (6.8 +/- 0.8). In group III diabetics, upright PRA was 4.0 +/- 0.5, significantly lower than that in any other group. These results suggest that (1) PRA is normal in normotensive diabetics, (2) upright PRA in diabetics with hypertension but no nephropathy is similar to that in essential hypertension, and (3) patients with diabetes, hypertension, and nephropathy have "low renin hypertension," explaining the virtual absence of malignant hypertension in this group. Although the major mechanism for this low PRA may be volume expansion, indicating the need for potent diuretics, other mechanisms include hyalinization of the afferent arteriole, decreased cathecholamine stimulation of renin release, and inadequate conversion of prorenin to renin.

Plasma renin activity and blood volume in uncontrolled diabetes. Ketoacidosis, a state of secondary aldosteronism.

The renin-angiotensin-aldosterone system was evaluated in two types of uncontrolled diabetes: a) diabetic ketoacidosis, and b) nonketotic hyperglycemia. In thirteen patients with ketoacidosis, mean plasma renin activity (PRA) was 58 plus or minus 12 (S.E.M.) ng. per milliliter per hour and in four patients, plasma aldosterone was 82 plus or minus 17 ng. per 100 ml. Corresponding values for upright salt-depleted subjects were 13 plus or minus 2 and 62 plus or minus 8. In eleven diabetics with nonketotic hyperglycemia (mean glucose 318 plus or minus 19 mg. per cent), mean blood volume was 4,660 ml. and PRA 2.1 plus or minus .7. After control of the diabetes (mean glucose 129 plus or minus 13) blood volume was 4,553 ml. and PRA 3.3 plus or minus 1 (NS). The results suggest that: 1) diabetic ketoacidosis is a state of severe secondary aldosteronism, 2) no significant change in blood volume or PRA occurs during short periods of hyperglycemia, and 3) insulin is not necessary for renin release.

Vascular reactivity to angiotensin II and to norepinephrine in diabetic subjects.

Vascular responsiveness to infused angiotensin II and to norepinephrine was determined in 14 normal subjects and two groups of diabetic subjects, 16 with no clinically detectable diabetic complications and 14 with diabetic retinopathy but no clinical evidence of nephropathy. All were maintained on a 100-mEq. -Na- 100-mEq. -K diet. Serum electrolytes, 24-hour urinary sodium, creatinine clearance, and plasma renin activity did not differ significantly among the groups. Group mean baseline diastolic pressure in those with retinopathy was higher than in normal subjects but no significantly different from that of uncomplicated diabetics. The pressor dose of angiotensin II (ng./kg./min. to increase diastolic blood pressure 20 mm. Hg) for each group respectively was 11.5 +/-0.9, 12.9+/- 1.3, and 8.3 +/- 1.3, and the slope of the dose-response curve (mm. Hg rise in blood pressure resulting from the infusion of 1 ng./kg./min. following the initial increment in blood pressure) was 2.0 +/-0.2, 1.6+/-0.2, 3.3+/- 0.6. For norepinephrine, the pressor doses were 163 +/- 24, 212+/-21, and123 +/- 11 and slopes were 0.17 +/- 0.03, 0.13 +/- 0.02, and 0.20 +/-0.02. Neither diabetic group differed significantly from normal subjects. Diabetics with retinopathy were more sensitive to angiotensin II, pressor dose (P less than 0.059) and slope (P less than 0.02), and to norepinephrine, pressor dose (P less than 0.006) and slope (P =0.05) than those without complications. These data suggest that vascular reactivity is enhanced in diabetics with retinopathy.

Retinal vascular reactivity to norepinephrine and angiotensin II in normals and diabetics.

Retinal arterial vasoconstriction induced by an infusion of angiotensin II or norepinephrine was investigated in eight normal controls (N), nine diabetics without retinopathy (DNR), and 10 diabetics with retinopathy (DR) by color fundus photographs taken before and after the infusions. Image analysis was done by a semiautomated computerized microdensitometer using a videoscanner. Normal controls and diabetics without retinopathy had a significant reduction in diameter compared with diabetics with retinopathy, who failed to constrict arterioles in response to either vasopressor. The mechanism of this phenomenon is unclear. Semiautomated computerized microdensitometry is reproducible and appears to be a sensitive technique to evaluate the vascular reactivity of the retinal vasculature.

Treatment selection considerations for the hypertensive diabetic patient.

Hypertension occurs with twice the frequency in the diabetic population as compared with the general nondiabetic population. Treatment of hypertension in diabetics can be complicated by diabetic complications and the potential for adverse effects from selected antihypertensive drugs. A rational approach to antihypertensive therapy in diabetics with or without concurrent diabetic complications incorporates a "stepped" approach to therapy that includes alternative step 1 agents (eg, angiotensin-converting enzyme inhibitors and calcium channel blockers) rather than traditional agents (eg, diuretics and beta-blockers). Evolving evidence with angiotensin-converting enzyme inhibitors reveals that they do not exacerbate complications of diabetes mellitus and also may arrest or slow the progression of diabetic nephropathy. Treatment algorithms for a stepped approach to the management of the hypertensive diabetic patient are proposed.

Excess mortality associated with diuretic therapy in diabetes mellitus.

OBJECTIVE: To determine whether the high mortality among diabetic patients receiving treatment for hypertension can be explained by associated risk factors or must be attributed to a deleterious effect of antihypertensive treatment. DESIGN: Cohort analytic study with a median follow-up of 4.5 years. SETTING: Outpatients with diabetes and severe retinopathy who were enrolled in a multicenter, randomized clinical trial of laser treatment to prevent blindness had ophthalmologic examinations every 4 months and annual medical examinations that included measurement of blood pressure and recording of anti-hypertensive treatment. Only 5.5% of the patients were unavailable for follow-up. When a patient died, the circumstances surrounding the death were reviewed and classified by a mortality review committee. PARTICIPANTS: --There were 759 participants in the study; they were white, were aged 35 to 69 years, and had normal serum creatinine levels at the baseline examination. MEASUREMENTS AND MAIN RESULTS: --Patients were classified into five groups according to information recorded at the baseline and first annual follow-up examinations: normotensive (diastolic blood pressure less than 90 mm Hg), untreated hypertensive, hypertensive treated by diuretics alone, hypertensive treated by other agents alone, and hypertensive treated by both agents. Cardiovascular mortality was higher in patients treated for hypertension than in patients with untreated hypertension. The excess was primarily found in patients treated with diuretics alone, although that group had the lowest blood pressure with treatment. After adjusting for differences in risk factors, cardiovascular mortality was 3.8 times higher in patients treated with diuretics alone than in patients with untreated hypertension (P less than .001). CONCLUSIONS: --In individuals with diabetes, intervention with diuretics to reduce hypertension is associated with excess mortality. Until there is a clinical trial showing a beneficial effect of diuretic treatment in diabetic patients, there is urgent need to reconsider its continued usage in this population.

Amyloid deposition in serosal membranes. Its occurrence with cardiac tamponade, bilateral ureteral obstruction, and gastrointestinal bleeding.

Widely dispersed amyloid deposition of the serosa occurring in a patient produced impairment of cardiac, renal, and gastrointestinal integrity by encasement. This patient survived the acute complications of both cardiac tamponade and bilateral ureteral obstruction due to amyloid. This case demonstrates the utility of resorting to aggressive life-support mechanisms despite an apparently systemic spread of amyloid disease in selected cases.

The hypertensions of diabetes.

Patients with diabetes mellitus may have any one of several forms of hypertension. These include essential hypertension, systolic hypertension of three varieties, the hypertension associated with diabetic nephropathy ("diabetic hypertension"), and the hypertension associated with neuropathy (supine hypertension with orthostatic hypotension). Because there are differences in the hypertensive mechanisms in each of these hypertensions, the use of antihypertensive medications should be tailored to the type of hypertension present. In this review, the rationale for treating hypertension in the diabetic will be discussed, the mechanisms of action and potential side effects of antihypertensive drugs peculiar to the diabetic will be outlined, and specific antihypertensive therapy programs based on the mechanisms involved in producing each of the hypertensions will be detailed.

Risk of proliferative diabetic retinopathy in juvenile-onset type I diabetes: a 40-yr follow-up study.

The development of proliferative diabetic retinopathy was studied in three cohorts consisting of 292 patients with recent juvenile-onset, type I (insulin-dependent) diabetes who were followed 20-40 yr beginning in 1939, 1949, and 1959. The risk of this severe eye complication was almost nonexistent during the first 10 yr of diabetes, rose abruptly to its maximum level (approximately 30/100 person-years), and remained at that level for the next 25 yr. This pattern did not vary with sex, age at onset of diabetes, or level of glycemic control during the first 5 yr of diabetes. However, the risk of proliferative retinopathy was strongly related to the level of glycemic control during the several years preceding onset of this complication. This was a dose-dependent relationship, with patients in the highest quartile of the distribution of the index of frequency of hyperglycemia having a 10-fold higher risk than individuals in the lowest quartile. A virtually identical pattern was observed in patients who developed diabetes in 1959 as was observed in those who developed diabetes in 1949 or 1939. In contrast, diabetic nephropathy as evidenced by persistent proteinuria showed a lower incidence in the 1959 than in the 1939 cohort. In conclusion, these incidence data do not support the notion that the risk of proliferative retinopathy is mainly a function of duration of diabetes. Instead, the pattern of occurrence of this severe eye complication in type I diabetes suggests that the process leading to the development of proliferative retinopathy consists of two or more stages and that progression through each stage may be governed by different factors.

Reversible acute pulmonary edema due to uncontrolled hyperglycemia in diabetic individuals with renal failure.

On eight separate occasions, four functionally anephric diabetic patients (on maintenance hemodialysis) experienced episodes of severe hyperglycemia with acute interstitial and alveolar pulmonary edema demonstrated clinically and by chest x-ray without electrocardiographic or enzymatic evidence of an acute myocardial lesion. Three patients had normal stress 201T1 scanning. The fourth patient, who experienced three such episodes, had normal coronary angiograms and only a mild elevation of the left-ventricular end-diastolic pressure. Clinical and chest x-ray improvement were immediate following insulin therapy and control of hyperglycemia, without phlebotomy or dialysis. Since these episodes were observed during a 1-yr period, this syndrome may be more common than suspected. It is concluded that in functionally anephric diabetic individuals: (1) pulmonary edema can be precipitated by uncontrolled diabetes; (2) endogenous fluid shifts may contribute to the cause of acute pulmonary edema; (3) clinical and radiologic improvement can be achieved with adequate insulin therapy; and (4) blood glucose levels should be monitored and controlled in diabetic patients with renal failure.

Is insulin the link between hypertension and obesity?

Oral glucose tolerance tests with plasma glucose and insulin determinations were performed on 195 patients with impaired glucose tolerance. Patients were divided into three groups according to blood pressure levels: normal, below 140/90 mm Hg; diastolic hypertension, diastolic pressure above 90 mm Hg; and systolic hypertension, systolic pressure above 140 and diastolic pressure below 90 mm Hg. Sex, age, and glucose levels were similar among the groups. By contrast, serum insulin levels were significantly elevated for the patients with diastolic hypertension (p less than 0.01). This difference persisted after correction for body weight. These results suggest a causal relationship between the level of circulating insulin and diastolic blood pressure, and support the concept that hyperinsulinemia may be the common link in the clustering of hypertension, diabetes, and obesity.

The changing natural history of nephropathy in type I diabetes.

Events in the natural history of diabetic nephropathy (including the onset of persistent proteinuria and end-stage renal failure) were studied in a cohort of 292 patients with juvenile-onset type I diabetes who were followed for 20 to 40 years. The risk of persistent proteinuria increased rapidly between the fifth and 15th years of diabetes and declined thereafter. This pattern suggests that susceptibility to this complication was limited to a subset of patients and was exhausted over time. Patients with the most frequent severe hyperglycemia (the highest quartile) during the first 15 years of diabetes had a risk of persistent proteinuria that was four and a half times higher than that for those with the least frequent hyperglycemia (the lowest quartile). Patients whose diabetes was diagnosed in the 1930s had twice the risk of persistent proteinuria as those in whom the condition was diagnosed in later decades. Once persistent proteinuria appeared, progression to renal failure almost always followed. Half reached this stage within 10 years, and the interval for progression did not vary according to sex, frequency of hyperglycemia, or calendar year of diagnosis of diabetes. This period, however, was significantly shorter (eight versus 14 years) for patients whose diabetes was diagnosed after puberty than for those who were younger at onset. In conclusion, the development of diabetic nephropathy consists of at least two stages. The onset of proteinuria, although related to the level of exposure to hyperglycemia, appears to be influenced by genetic and/or environmental factors. The second stage, progression to renal failure, seems to be influenced by processes related to maturation or aging.

Evolving natural history of coronary artery disease in diabetes mellitus.

White diabetic patients are at high risk of developing coronary artery disease (CAD). The natural history of CAD in insulin-dependent (ID) and noninsulin-dependent (NID) diabetes mellitus (DM) is reviewed to gain insight into the mechanisms responsible for the development of premature or accelerated atherosclerosis in diabetic patients. In both IDDM and NIDDM, the risk of CAD increases with lengthening duration of diabetes; the risk, however, does not grow as a constant multiple of the nondiabetic risk of CAD, suggesting that the cumulative exposure to diabetes plays a significant role as a risk factor for CAD only in a subset of patients. This is consistent with the hypothesis that the diabetic milieu has an impact on the progression of atherosclerotic lesions but not on their initiation. This hypothesis is corroborated further by the observation that CAD does not occur in diabetic patients in populations with a low risk of CAD among nondiabetic patients. The component of the diabetic milieu responsible for promotion of atherosclerotic lesions is unknown. There is evidence, however, of a direct or indirect role of hyperinsulinemia in this process.

Systemic hypertension, diabetes mellitus and the kidney.

Diabetic nephropathy is manifested by albuminuria, hypertension and progressive loss of renal function. Only one-third of patients with insulin-dependent diabetes mellitus of juvenile onset develop nephropathy and the risk of nephropathy does not increase with increasing duration of diabetes. Hypertension occurs almost exclusively in patients with nephropathy. Therefore, there is a subset of patients at risk for both nephropathy and hypertension. It is important to identify the patients destined to develop nephropathy, to define the pathophysiology responsible for the nephropathy in this subset of patients and to develop programs to interrupt the pathophysiology early in its course and hopefully prevent the progression to end-stage renal failure. Potential markers to identify patients who will develop nephropathy include a family history of hypertension, increased glomerular filtration rate and renal mass and presence of significant microalbuminuria. Studies are needed to evaluate various classes of drugs for their efficacy in altering the pathophysiologic hemodynamic changes leading to nephropathy.

Acute myocardial infarction in diabetes mellitus and significance of congestive heart failure as a prognostic factor.

Diabetes mellitus has been associated with high mortality rates in patients with acute myocardial infarction (AMI). To better define prognosis in this population, the clinical course of 183 diabetics with AMI was studied. In-hospital mortality for all patients was 28% (52 of 183 patients). Mortality was significantly higher in patients with prior AMI than in patients without prior AMI (41 vs 18%, p less than 0.01) and was significantly higher in women than in men (37 vs 19%, p less than 0.01). The 2-fold increase in mortality among diabetic women was observed both in patients with and without prior AMI. The excess mortality among diabetic women was attributable to their increased risk for severe congestive heart failure (CHF) and cardiogenic shock. Death due to CHF occurred in 22% of all diabetic women with AMI compared with 6% of the diabetic men (p less than 0.01). Death resulting from complications other than CHF was similar for both sexes. There were no male-female differences in the history of prior AMI, systemic hypertension, obesity, nephropathy, frequency of Q-wave AMI, anterior AMI or peak creatine kinase levels to account for the high risk for CHF in diabetic women. It is therefore concluded that diabetic women with AMI are at increased risk for death due to CHF, and that this risk is not readily attributable to known conditions associated with CHF.

Magnitude and determinants of coronary artery disease in juvenile-onset, insulin-dependent diabetes mellitus.

The risk of premature coronary artery disease (CAD) and its determinants were investigated in a cohort of 292 patients with juvenile-onset, insulin-dependent diabetes mellitus (IDDM) who were followed for 20 to 40 years. Although patients with juvenile-onset IDDM had an extremely high risk of premature CAD, the earliest deaths due to CAD did not occur until late in the third decade of life. After age 30 years, the mortality rate due to CAD increased rapidly, equally in men and women, and particularly among persons with renal complications. By age 55 years the cumulative mortality rate due to CAD was 35 +/- 5%. This was far higher than the corresponding rate for nondiabetic persons in the Framingham Heart Study, 8% for men and 4% for women. Angina and acute nonfatal myocardial infarction followed a similar pattern, as did asymptomatic CAD detected by stress test, so that their combined prevalence rate was 33% among survivors aged 45 to 59 years. Age at onset of IDDM and the presence of eye complications did not contribute to risk of premature CAD. This pattern suggests that juvenile-onset diabetes and its renal complications are modifiers of the natural history of atherosclerosis in that although they profoundly accelerate progression of early atherosclerotic lesions to very severe CAD, they may not contribute to initiation of atherosclerosis.