David B. Case

Percutaneous Transluminal Renal Angioplasty in Renovascular Hypertension Due to Atheroma or Fibromuscular Dysplasia

We attempted percutaneous transluminal renal angioplasty in 89 patients with hypertension and renal-artery stenosis (including 51 with atheromatous and 31 with fibromuscular stenoses) who were then followed for an average of 16 months (range, 4 to 40). Angioplasty was technically successful in 87 per cent of the fibromuscular stenoses and in 57 per cent of the unilateral atheromatous stenoses but in only 10 per cent of the bilateral atheromatous stenoses. After successful angioplasty, blood pressure was reduced to normal or improved in 93 per cent of the patients with fibromuscular dysplasia and in 84 per cent of the patients with atheromatous disease. Angiographic follow-up at an average of 21.8 months in 15 patients showed persistent relief of the stenoses and a 12 per cent average increase in kidney size. Renal angioplasty is effective for long-term control of hypertension in patients with renal-artery stenosis due to fibromuscular dysplasia or unilateral non-ostial atheroma.

Possible Role of Renin in Hypertension as Suggested by Renin-Sodium Profiling and Inhibition of Converting Enzyme

To block renin activity, a nonapeptide converting-enzyme inhibitor was given to 65 seated hypertensive patients. Depressor responses occurred only when control plasma renin activity exceeded 2 ng of angiotensin I per milliliter per hour and correlated directly in amplitude with control plasma renin activity and with induced increments in activity (P less than 0.001 for both). Depressor responses, like renin activity, were characteristic for renin subgroups as defined by renin-sodium profiling. Before and after sodium deprivation, the nonapeptide reduced diastolic pressure in all patients with high renin (by 17.3 and 19.8 per cent) and most patients with normal renin (by 9.1 and 17.7 per cent). Low-renin patients remained unresponsive. This enzyme blockade may cause bradykinin accumulation. But if, as seems likely, depressor responses are due to blockade of angiotensin II formation, the results indicate that, irrespective of sodium balance, measurements of plasma renin activity reflect its contribution to blood-pressure maintenance. The results suggest broad participation of the renin system in common forms of hypertension.

The captopril test for identifying renovascular disease in hypertensive patients

To develop a screening test for identifying renovascular hypertension, the blood pressure and plasma renin activity responses to an oral test dose of captopril were studied in 246 quietly seated hypertensive patients. The following criteria were developed that exploit the hyperresponsiveness of renin secretion in renovascular hypertensive patients: a 60-minute post-captopril plasma renin activity of 12 ng/ml per hour or more and an absolute plasma renin activity increase of 10 ng/ml per hour or more, along with a 150 percent increase in plasma renin activity (or a 400 percent increase if the baseline plasma renin activity was below 3 ng/ml per hour). Retrospectively, the test identified, among 200 hypertensive patients without evidence of renal dysfunction, all 56 patients with proved renovascular disease. In this group, false-positive results occurred only in two of 112 patients with essential hypertension and in six with secondary hypertension. Nine untreated patients had blood pressure levels of less than 160/100 mm Hg. The test was neither as sensitive nor specific in the 46 patients with renal insufficiency. This study demonstrates that the renin response to oral captopril is a useful screening test for identifying patients with unilateral or bilateral renovascular disease. Since the test also characterizes the renin dependency of the hypertension, it may have other diagnostic and therapeutic uses.

Usefulness and limitations of saralasin, a partial competitive agonist of angiotensin II, for evaluating the renin and sodium factors in hypertensive patients

Saralasin was infused into 52 untreated hypertensive patients. Immediate, transient pressor responses occurred in 94 per cent followed by a more gradual sustained change in blood pressure reaching an apogee in about 20 minutes. Most (86 per cent) patients with high renin values had sustained depressor responses irrespective of sodium balance. In contrast, during a normal sodium intake, the drug produced a neutral (45 per cent) or mildly pressor (50 per cent) response in patients with normal renin and pressor responses in patients with low renin values. Sodium depletion abolished pressor responses and resulted in depressor responses in 64 per cent of the patients with normal renin values. The pretreatment angiotensin level appeared to determine direction and amplitude of the response to saralasin, since increases and decreases in diastolic pressure exhibited a highly significant relationship to the control renin lever (r = 0.80, p less than 0.001). Above a neutral range of control renin values, from 2 to 7 ng Al/ml/hour, depressor responses were the rule, and below it pressor responses were consistent. Sodium balance also appeared to determine the amplitude of the response. In a subset of patients with similar renin values (range 1.4 to 2.2 ngAl/ml/hour), the induced pressor responses correlated directly with the 24-hour sodium excretion (p less than 0.05). For all patients, the induced pressure change also was related to the rate of sodium excretion (r = 0.53, p less than 0.001). The data suggest that saralasin behaves as a partial competitive agonist of angiotensin II. For this reason, saralasin testing provided only a rough physiologic validation for renin profiling. Thus, depressor responses expose most patients with high renin values. Neutral responses occur in many patients with normal renin and intermediate renin values. But pressor responses occur in subjects with either low or normal renin levels and they may reflect sodium and volume excess associated with a partial or relative absence of renin. Accordingly, due to its partial agonism, saralasin testing under-estimates the renin factor. Hence, the drug cannot be used to identify or exclude renin involvement in the blood pressure in the large majority of hypertensive patients who do not exhibit depressor responses. For them an agent devoid of agonism is required. Moreover, prior sodium depletion as a device to increase the frequency of depressor responses to saralasin does not measure intrinsic renin dependency of the blood pressure but rather the reactivity of the system to sodium depletion.

Estimating renin participation in hypertension: Superiority of converting enzyme inhibitor over saralasin

This study was designed to examine more closely the differences in blood pressure responses in hypertensive patients to two agents which block the renin-angiotensin system. Accordingly, 39 seated patients received under the same conditions both saralasin, an octapeptide competitive antagonist of angiotensin II, and the nonapeptide converting enzyme inhibitor, SQ20881, which blocks the generation of angiotensin II from angiotensin I. A second component of the study involved administration of these agents in 10 addtional studies in anephric subjects. Although both agents produced maximal responses in blood pressure that correlated well with each other (p less than 0.001) and with the pretreatment plasma renin levels (p less than 0.001), analysis of the results by renin subgroups revealed significant differences. Thus, both drugs lowered the diastolic pressures of patients with high renin levels, but but converting enzyme inhibitor produced changes of greater amplitude (p less than 0.05). In contrast, saralasin was consistently pressor in both patients with low renin levels and anephric patients in whom converting enzyme blockade preduced no significant changes in blood pressure. Another impressive disparity in the responses to the two agents occurred in the group with normal renin levels in whom saralasin produced either neutral or pressor responses (mean change was +2.0 +/- 1.5 standard error of the mean (SEM) per cent control diastolic pressure) whereas the converting enzyme inhibitor consistently induced depressor responses (mean change was -10.2 +/- 1.2 per cent, p less than 0.001). Altogether, the results suggest that converting enzyme inhibitor tests for angiotensin II-dependent blood pressure with more sensitivity than the partial agonist saralasin. Moreover, it is unlikely that the differences between the responses to the two agents were due to bradykinin accumulation, since depressor responses to converting enzyme inhibitor were not observed in the patients with low renin levels and the anephric patients.

Unexpected pressor responses to propranolol in essential hypertension: An interaction between renin, aldosterone and sympathetic activity

The blood pressure response to propranolol treatment was analyzed retrospectively in 187 patients with benign essential hypertension. In most patients (102 patients, 54 per cent) systolic and/or diastolic blood pressure was decreased by more than 10 per cent (responders). No significant change in blood pressure occurred in 35 per cent (65 patients) of the patients (nonresponders). Surprisingly, in 20 patients (11 per cent) systolic (8 patients) and/or diastolic (14 patients) blood pressure was increased by more than 7 per cent (pressor-responders). All three subgroups received similar amounts of propranolol and irrespective of the effect on the blood pressure, propranolol produced a similar reduction in pulse rates, suggesting similar degree of beta blockade. The three subgroups did not differ in their clinical characteristics, except that the nonresponders were significantly older than the responders. Pretreatment renin values were highest in the responders, somewhat lower in the nonresponders and significantly lower in the pressor-responders. In a representative subset of 66 patients, control and treatment values for plasma renin activity and aldosterone excretion were compared. The responders had the most pronounced decreases in both renin and aldosterone. In striking contrast, no significant changes were observed in the two hormones in those patients whose blood pressure levels rose. Moreover, in the pressor-responders, the drug produced the greatest increases in body weight, reflecting sodium retention. The differences in blood pressure responses observed in different patients may be explained by various interplays between the drug-induced suppression of renin and aldosterone, and the operation of unapposed or reactive alpha sympathetic activity. The latter is presumably active in all patients tending to cause vasoconstriction and hence an increase in peripheral resistance. In the pressor-responders such unopposed alpha-tone combined with the demonstrated lack of renin and aldosterone suppression with attendant fluid retention could work to produce the paradoxical pressor responses. In contrast, in those whose blood pressure levels drop, the drug-induced suppression of renin leads to decreased peripheral resistance despite the unopposed alphatone. The accompanying decrease in aldosterone limits sodium retention and contributes to the fall in blood pressure levels.

Predictive value and changes of renin secretion in hypertensive patients with unilateral renovascular disease undergoing successful renal angioplasty

Peripheral and renal vein renin activity was measured in 46 hypertensive patients with arteriographically diagnosed unilateral renal artery stenosis before and six months after technically successful renal angioplasty. The renin-sodium profile was high in 80 percent before angioplasty, fell in all patients, and became normal or low in 85 percent after angioplasty. Renal vein renin activity, which initially showed lateralization of renin secretion to the ischemic kidney with contralateral suppression, became normal. Renal vein renin activity was more reliable for predicting the therapeutic response when expressed as the increment of renin for each renal vein over the infrarenal vena caval value (sensitivity 74 percent, specificity 100 percent) than as the ratio between the two renal veins (sensitivity 62 percent, specificity 60 percent). The predictive value of renal vein renin activity is poor when plasma renin activity is stimulated by long-term administration of captopril. These data support the usefulness and define the limitations of peripheral and renal vein renin measurements in selecting patients for treatment by renal angioplasty.

Reactive Hyperreninemia in Renovascular Hypertension After Angiotensin Blockade with Saralasin or Converting Enzyme Inhibitor

Baseline plasma renin activity and responses to saralasin and converting enzyme inhibitor SQ 20881 (teprotide) in 47 untreated patients with surgically correctable renovascular hypertension were compared to those in 100 patients with high- and normal-renin essential hypertension. All 32 renovascular patients on normal sodium intake had high renin-sodium profiles and renin values greater than or equal to 5 ng angiotensin I/mL.h, as compared to 20 of 64 with essential hypertension. Diagnostic discrimination was greatly enhanced by infusion of saralasin or SQ 20881, which elicited marked reactive hyperreninemia in 31 of 32 renovascular patients but in only two of 64 with essential hypertension. Reactive hyperreninemia appeared to be more a specific test for renovascular hypertension than depressor responses. Prior dietary sodium depletion abolished this specificity. The results suggest that after initial screening with renin measurements, testing with angiotensin blocking agents may be a useful secondary screening procedure for more invasive and definitive procedures.

Possible Role of Increased Blood Viscosity in the Hemodynamics of Systemic Hypertension

It has long been recognized that the viscosity of a fluid contributes importantly to the resistance to its flow. For .150 years, the Poiseuille equation has drawn attention to resistance to flow in a tube as directly related to the viscosity of the fluid as well as the tube’s geometry. 1 In contrast to the extensive studies of vascular geometry in hypertension, relatively little attention has been paid to the possible contribution of altered blood viscosity to elevated vascular resistance in systemic hypertension. A few studies have reported elevated levels of whole blood viscosity (WBV) in patients with essential hypertension.2‐5 However, as with all studies comparing clinical patients with recruited normal volunteers, it is uncertain whether subject selection may have influenced results. Specifically, it is unclear whether WBV is higher in unselected patients with essential hypertension than in apparently normal adults from the same population. Furthermore, it is also unknown whether the elevation in WBV is proportionate to the increase in peripheral resistance in such patients and thereby could play a role in the pathogenesis of essential hypertension.6

Use of first-dose response or plasma renin activity to predict the long-term effect of captopril: identification of triphasic pattern of blood pressure response.

A triphasic pattern of blood pressure response was observed in 13 of 26 patients treated with captopril. Pressure fell after the first dose in all but 3 patients, reaching a minimum by 90 min. Over the next several days, pressure either remained at this level (n = 13) or returned towards control levels (n = 13) even with increased dosage. Blood pressure then fell gradually, usually reaching a level by 10 days that was equal to or slightly lower than that after the first dose. The secondary rise in blood pressure was more frequent and pronounced in patients who had larger initial responses and higher renin levels. The transient increase in pressure could not be explained by failure of blockade of the renin system, since aldosterone excretion was maximally suppressed by the second day of treatment. The data indicate that both the blood pressure response to the first dose and the renin level can be used to predict the long-term response to captopril.