Walter M. Kirkendall

The Effect of Treatment on Mortality in Mild Hypertension: Results of the Hypertension Detection and Follow-up Program

In the Hypertension Detection and Follow-up Program, 7825 (71.5 per cent) of the 10,940 participants had diastolic blood pressures averaging between 90 and 104 mm Hg on entry into the study and were designated Stratum 1. Half were referred to their usual source of care in the community (the referred-care group), and half were treated intensively in special clinics (the stepped-care group). Five-year mortality in the Stratum 1 patients given stepped care was 20.3 per cent lower than in those given referred care (P less than 0.01). Particularly noteworthy was the beneficial effect of stepped-care treatment on persons with diastolic pressures of 90 to 104 mm Hg who had no evidence of end-organ damage and were not receiving antihypertensive medication when they entered the study. This subgroup had 28.6 per cent fewer deaths at five years among those treated with stepped care than among those treated with referred care (P less than 0.01). These findings support a recommendation that in patients with mild hypertension, treatment should be considered early, before damage to end organs occurs.

Hypertensive crisis managed by computer controlled infusion of sodium nitroprusside: a model for the closed loop administration of short acting vasoactive agents.

Abstract Nitroprusside infusion has been controlled by computer in 12 cases of hypertensive crisis. Pretreatment mean arterial pressure varied from 134 to 165 mm Hg. Nitroprusside infusion was commenced manually, a set point for mean arterial pressure specified and computer control commenced. Each 2 min the computer compares mean arterial pressure with the set point. For mean arterial pressures 10 mm Hg or more above the set point, the infusion rate increases by 5%. For mean arterial pressures 10 mm Hg or more below the set point, the infusion is decreased in rate or stopped depending on the level of pressure. The percentage of time mean arterial pressure was maintained within ±10 mm Hg of the set point averaged 75%, within a ±15 mm Hg range 88%, and within a ±20 mm Hg range 94%. The system has been successful in the management of patients with complicated hypertension.

Comparative assessment of first-line agents for treatment of hypertension

Abstract To compare the safety and efficacy of isradipine as an antihypertensive drug, five studies were performed with other antihypertensive drugs. In each, isradipine was given in doses of 2.5 to 10 mg twice daily and its effects were compared with those of placebo, propranolol, prazosin, and hydrochlorothiazide. The studies were randomized and double-blinded, employing either a fixed or forced titration. Studies were designed with a three-week placebo washout period followed by four to 10 weeks of active therapy. Isradipine was administered to 288 patients and resulted in a mean decrease in diastolic blood pressure of 16.2 mm Hg; in 81 percent of the patients it decreased by more than 10 mm Hg. Corresponding values for the other drugs tested were: placebo (n = 78), 5.9 mm Hg and 32 percent; propranolol (n = 31), 9.8 mm Hg and 39 percent; and prazosin (n = 33), 13 mm Hg and 69 percent. Isradipine was generally well tolerated, with few reported side effects.

Treatment of hypertension in the elderly

Investigation of preventive measures for hypertension and atherosclerosis is a geriatric medicine priority. While the causes of both isolated systolic hypertension and conventional systolic and diastolic hypertension in the elderly are well defined, the benefits of lowering blood pressure are not. Evidence to support the treatment of symptomatic hypertension is convincing for men 60 years of age; it is not for women in this age group. The need to treat hypertension, particularly isolated systolic hypertension in patients above 75 years old, is still not resolved. Isolated systolic hypertension in older patients is at least as strong a risk factor for cardiovascular disease as is diastolic hypertension. Ongoing trials may answer these questions; in the meantime, drug therapy in this group will vary widely. The elderly hypertensive is more likely than the younger hypertensive to have other diseases; diagnosis of these disorders is crucial. Hypertension arising de novo late in life warrants a search for underlying and possibly remedial causes. Antihypertensive drug therapy to relieve symptoms is difficult to justify, because most elderly hypertensive patients are asymptomatic; however, it has been shown to delay morbid and fatal complications of hypertension. Appropriate therapy for the elderly hypertensive must be individualized and should be associated with few or no side effects. The thiazides are the preferred diuretics for long-term treatment of hypertension in the elderly. Beta blockers are attractive because they are cardioprotective, counter the end organ effect of catecholamines and reduce angina; however, some decrease cardiac output, increase peripheral resistance, decrease renal blood flow and cause fatigue.(ABSTRACT TRUNCATED AT 250 WORDS)

Purification of human renin and inhibition of its activity by pepstatin

Several proteases from human kidney tissue were partially purified by ammonium sulfate precipitation followed by Sephadex G-75 gel filtration chromatography. The incubations of column fractions with 14C-tetradecapeptide renin substrate indicated four major renin activity peaks between the molecular weights of 25,000 and 80,000. The highest specific activity was found in Fraction B (mol. wt 39,500). Significant renin-like activity was also found in Fraction A (mol. wt 58,000) and Fraction C (mol. wt 33,500). None of the fractions contained angiotensinase activity. Disc-gel electrophoresis indicated that Fractions B and C were heterogeneous. The conversion of 14C-tetradecapeptide renin substrate to angiotensin I by major fractions was differentially inhibited by low concentrations of pepstatin. Both the rate of substrate conversion and the sensitivity to pepstatin were influenced by pH. Generally, the proteases were more sensitive to pepstatin at physiological pH. Regardless of pH, all of the kidney proteases were completely inhibited by 10−3 M pepstatin. The conversion of human substrate by human plasma proteases was found to be even more sensitive to pepstatin. The concentration of 10−5 M pepstatin essentially eliminated plasma renin activity. These results indicate that pepstatin can serve as an efficient inhibitor of both human kidney and plasma renin proteases and as such will be useful in the study of the kinetics of these systems in both research and clinical situations.

Structure of neutral glycerides and phosphoglycerides of human kidney

Abstract 1. 1. Neutral lipids and phospholipids of human kidney have been isolated and the fatty acid composition of each determined. 2. 2. Triglycerides were fractionated into 7 bands by argentation chromatography. The major class (49%) was saturated, monoene, monoene. Stereospecific analysis revealed that both positions 1 and 2 contained an approximate ratio of 1:1 saturated to unsaturated fatty adds. 3. 3. Positional distribution of fatty acids in phosphatidylcholine, the major phospholipid component (27.2%), was determined by phospholipase A2 and pancreatic lipase hydrolysis. 4. 4. Overall results indicated similarities and differences when compared to kidney lipids of other mammalian species.

Renin as a risk factor for atherogenesis: Effects of hypercholesterolemia and two-kidney-one-clip hypertension in the rabbit

Four groups of New Zealand rabbits were used to study the effect of plasma renin activity (PRA) on atherogenesis. Control groups were fed normal rabbit chow (Group I) or chow supplemented with 0.25% cholesterol and 0.75% corn oil (Group II). The two-kidney--one-clip (2K-1C) hypertensive model was produced in 2 additional groups; Group III (normal diet) and Group IV (atherogenic diet). The latter 2 groups were subgrouped according to PRA levels. Each group was examined over a 7-month period. Group II became hyperlipidemic and developed extensive lipoidal vascular lesions. Mean arterial pressure remained normal throughout the experimental period; PRA fell below normal. Group III and Group IV rabbits developed sustained hypertension irrespective of circulating PRA. The atheromas of Group III were predominantly microscopic and fibromuscular; the extent of aortic and coronary artery involvement was independent of renin response. The most extensive and complicated atheromas were seen in the 2K-1C rabbits consuming the atherogenic diet (Group IV). The lesions were mostly lipoidal, although some were fibromuscular. These results demonstrated that cardiovascular lesions and atherogenesis were exacerbated in the 2K-1C rabbits on a high cholesterol diet; however, PRA was excluded as the cause.

Cortical and medullary lipids of normal and nephrosclerotic human kidney

Abstract 1. 1. Major lipid classes from cortical and medullary zones of normal and nephrosclerotic human kidneys have been isolated and the fatty acid composition of each determined. 2. 2. The nephrosclerotic tissue contained two times more total lipid than the normal kidney but, irrespective of kidney pathology, phospholipids were the major cortical lipids and neutral lipids were the predominant lipids in medullary zones. 3. 3. Human kidney contained large amounts of phosphatidylcholines, phosphatidylethanolamines and sphingomyelins and although these were slightly increased in the sclerotic kidney, anatomical differences in phospholipid content were not significant. 4. 4. Quantitative differences between the zones of normal kidney were found with triglycerides, diglycerides. free fatty acids and cholesterol; overall, the sclerotic tissue contained more triglycerides and small amounts of cholesterol esters with less significant regional differences. 5. 5. Palmitic, oleic and stearic acid were the major fatty acids of neutral lipids; these plus linoleic acid were prevalent in phospholipids.

RENIN AS A PREDICTOR OF HYPERTENSIVE COMPLICATIONS

Prior to the beginning of this decade, the interest in plasma renin activity (PRA) was mainly because of its association with malignant hypertension, renovascular hypertension, and primary aldosteronism. Considerable research effort was expended in defining proper PRA assay methods. The majority of the clinical studies were aimed at appraising the usefulness of PRA measurements, both in terms of screening patients for renovascular involvement as a basis for their hypertension (peripheral PRA), and for detecting specific, functional renovascular lesions (split renal vein plasma samples). Now, at the end of this decade, PRA assays can be performed reliably, if critical protocols are followed. Functional lesions can thus be isolated and surgical corrections can usually effect a cure for this group of patients. The value of peripheral PRA measurements as a hypertension screening device is still uncertain. In this paper, we examine the value of PRA in the prediction of cardiovascular risk.

Effect of human kidney lipids on human kidney renin activity.

Abstract The major lipids of human kidney tissue were isolated by solvent extraction, and the lipid composition was determined by thin-layer chromatographic techniques. The positional distribution of fatty acyl groups in ethanolamine and choline phosphatides was determined after enzymatic hydrolysis. Major phosphatides were assayed for plasmalogen content. Triglycerides were characterized by argentation chromatography. The fatty acyl composition of these lipids was also determined. The effect of intact triglycerides, phospholipids, 1- and 2-monoacyl phosphatides and ether lipids on renin activity in vitro was determined by incubations with 3-[U 14 C]valyl tetradecapeptide renin substrate. Kidney triglycerides, 1-monoacyl and 2-monoacyl phosphatidylethanolamines and phosphatidylcholines significantly inhibited renin activity. The renin-inhibitory effect of these lipids was comparable to inhibition by hog kidney phospholipid inhibitor. The intact phospholipids and cholesterol potentiated human kidney renin activity. Phosphatidylserines and synthetic glyceryl ether lipids have no significant effect. These results indicate that lipid-induced inhibition of human renin activity does not require the ethanolamine moiety, acyl group unsaturation, or the presence of a hydroxyl group at the 2-position. Additionally, no specific structure-activity relationships can describe lipid-renin interactions.