Gordon P. Guthrie

Serum Lipids and Incidence of Coronary Heart Disease Findings From the Systolic Hypertension in the Elderly Program (SHEP)

BACKGROUND The association of serum lipids with coronary heart disease has been studied extensively in middle-aged men and, to a lesser extent, in similar women. Less well defined are lipid variables predictive of CHD in individuals of age > or = 60 years. METHODS AND RESULTS The Systolic Hypertension in the Elderly Program recruited 4736 persons (mean age, 72 years; 14% were black; and 43% were men). Mean systolic and diastolic blood pressures were 170 and 77 mm Hg, respectively. Baseline mean total cholesterol was 6.11 mmol/L (236 mg/dL); HDL cholesterol, 1.39 mmol/L (54 mg/dL); and non-HDL cholesterol, 4.72 mmol/L (182 mg/dL). Triglyceride levels were 1.62 mmol/L (144 mg/dL) for fasting participants and 1.78 mmol/L for the total group. LDL cholesterol, estimated in fasting samples with triglycerides of < 4.52 mmol/L, averaged 3.98 mmol/L (154 mg/dL). Mean follow-up was 4.5 years. In multivariate Cox regression analyses, baseline total, non-HDL, and LDL cholesterol levels and the ratios of total, non-HDL, and LDL to HDL cholesterol were significantly related to CHD incidence. HDL cholesterol and triglycerides were not significant in these analyses. In fasting participants with triglyceride levels of < 4.52 mmol/L, a 1.03 mmol/L (40 mg/dL) higher baseline total, non-HDL, or LDL cholesterol was associated with a 30% to 35% higher CHD event rate. CONCLUSIONS The results of this study support the concept that serum lipids are CHD risk factors in older Americans.

Coronary Heart Disease Risk Factors in Men and Women Aged 60 Years and Older Findings From the Systolic Hypertension in the Elderly Program

BACKGROUND Coronary heart disease (CHD) is the most common cause of death in men and women aged 60 years and older. Although a number of studies support the concept that CHD risk factors that have been defined in younger adults are significantly associated with CHD events in older adults, others do not support this thesis, and further definition of the risk-factor concept in older adults is required. METHODS AND RESULTS The Systolic Hypertension in the Elderly Program recruited 4736 persons (mean age, 72 years); 14% were black, and 43% were men. Mean systolic and diastolic blood pressures were 170 and 77 mm Hg, respectively. About 13% of participants were current smokers; 10% had a history of diabetes; 5%, a prior myocardial infarction; 5% angina pectoris; 2.3%, intermittent claudication; and 7%, a carotid bruit. Mean total cholesterol value was 6.11 mmol/L. Mean follow-up was 4.5 years. In multivariate Cox regression analyses for CHD, variables that were significant were baseline total cholesterol value, smoking, history of diabetes, presence of carotid bruit, and treatment group in the trial. Active treatment yielded a 27% reduction in CHD risk. For each 1.03 mmol/L increase in total cholesterol value, there was an increase in risk of about 20%. Current smokers had a 73% increase, diabetics a 121% increase, and those with carotid bruit a 113% increase in CHD risk. CONCLUSIONS The results of this study support the concept that CHD risk factors are important in older men and women with isolated systolic hypertension.

Studies on the pathogenesis of Bartter's syndrome

There is no agreement concerning the primary pathogenetic event leading to Bartters syndrome. Free water clearance and distal fractional chloride reabsorption were abnormally low in our patient with Bartters syndrome. This series of investigations in this patient with Bartters syndrome and hypomagnesemia was undertaken to determine if the defect in chloride transport in the ascending limb and the associated renal potassium wasting was specifically related to potassium depletion, increased prostaglandin production or magnesium depletion. Neither potassium repletion, indomethacin administration nor magnesium repletion had an effect on the defect in free water clearance or in distal fractional chloride reabsorption. However, magnesium infusion eliminated renal potassium wasting. These observations suggest that the proximate cause of Bartters syndrome in this patient is a primary defect in the reabsorption of sodium chloride in the ascending limb and not renal potassium wasting. however, hypomagnesemia may contribute to the renal potassium wasting seen in this syndrome.

Clonidine in patients with diabetes and mild hypertension

Clonidine has been reported to adversely affect glucose tolerance in experimental animals and normal man. We assessed its short‐ and long‐term effects in 10 patients with both mild hypertension and diabetes mellitus. Patients were studied before and 10 wk after treatment with 0.1 mg clonidine twice daily, which induced reductions in blood pressure (from 148 ± 5/93 ± 2 mm H g sitting, to 125 ± 4/80 ± 2) and control of hypertension in all patients. Clonidine increased the glycemic response to intravenous glucose (incremental glucose AU C from 161 ± 13 to 184 ± 14) but did not significantly change long‐term diabetic control as assessed by weekly fasting serum glucose, glycosylated hemoglobin, and 24‐hr urinary glucose excretions before and after treatment. We conclude that low‐dose clonidine controlled blood pressure and impaired the response to an acute glucose challenge in mildly hypertensive, type II diabetic patients but did not adversely affect diabetic control over 10 wk.

Hypertension and aldosterone overproduction without renin suppression in Cushing's syndrome from an adrenal adenoma

Adrenal steroids and compenents of the renin-angiotensin system were measured before and after adrenalectomy in a woman with Cushings syndrome and hypertension from a functioning adrenocortical adenoma. Aldosterone, deoxycorticosterone and cortisol were produced in excess by the adenoma, and were measured in tumor tissue. High plasma renin substrate concentrations, and normal basal and furosemide-stimulated plasma renin activities and plasma renin concentrations which were present before surgery, decreased after adrenalectomy, and the hypertension diminished. The inappropriately normal levels of renin and potassium in this patient, despite autonomous aldosterone overproduction, suggest an ineffective mineralocorticoid action of aldosterone, possibly from interaction with her other adenoma-produced steroids. The decrease in components of the renin-angiotensin system suggests a partial renin-dependence of her hypertension.

Plasma renin activity, reactivity, concentration and substrate following hypertension during pregnancy. Effect of oral contraceptive agents.

SUMMARY Plasma renin activity is suppressed in approximately 25% of patients with essential hypertension, and the rate of in vitro angiotensin I production after addition of exogenous renin (renin reactivity) is increased in plasma of hypertensive patients. We have recently observed that blood pressure (116 ± 1.5/68 ± 1.7 mm Hg) of young women who had hypertension during a first pregnancy 3-6 years earlier (n = 63) was higher (p < 0.005) than blood pressure (109 ± 1.4/61 ± 1.7 mm Hg) of women who remained normotensive during pregnancy (n = 52). To determine if alterations of the renin-angiotensin axis observed in patients with established hypertension also occur in young adults with relatively high blood pressure, plasma renin activity (PRA), plasma renin concentration (PRC), plasma renin substrate (PRS) and plasma renin reactivity (PRR) were compared in these two groups of subjects. Overall, PRA and PRC were Inversely related to systolic blood pressure (p < 0.02). Excluding women on oral contraceptive agents, the PRA response to standardized treadmill exercise was suppressed (< 1.0 ng/ml/hr) in 19% of women with a history of hypertension during pregnancy and in no women who remained normotensive throughout a previous pregnancy; PRR did not differ [p > 0.8) in the two groups of young mothers (27.1 ng/ml/30 min ± 1.2 SK vs 26.2 ng/ml/30 mln ± 0.9 SE). Thus, renin suppression, but not increased PRR, precedes the onset of hypertension. Oral contraceptive usage was associated with higher systolic blood pressures, increased PRS, and low PRC. Highest blood pressures and lowest PRA occurred in women with a history of hypertension during pregnancy who were taking oral contraceptive agents at the time of study.

Effects of Prazosin and Clonidine on Sympathetic and Baroreflex Function in Patients with Essential Hypertension

Abstract: Prazosin, a peripherally active alpha‐adrenoceptor antagonist, and clonidine, a centrally active alpha‐adrenoceptor agonist, both reduce blood pressure but with different alterations in sympathetic nervous system activity. We studied the effects of monotherapy with either prazosin or clonidine in 10 and 30 patients, respectively, with essential hypertension. Prazosin reduced blood pressure without affecting heart rate or circulating plasma catecholamines. Sensitivity to injected phenylephrine was markedly reduced by prazosin, and sensitivity to isoproterenol was increased, whereas baroreflex sensitivity was not significantly altered. Blood pressure response to prazosin was correlated with basal plasma norepinephrine concentration (r = 0.64, P < 0.04). In contrast, clonidine reduced heart rates and plasma concentrations of both norepinephrine and epinephrine, increased the sensitivity to phenylephrine, and increased baroreflex sensitivity. Blood pressure response to clonidine was correlated with reduction in plasma norepinephrine concentration (r = 0.51, P < 0.004). Thus, blood pressure reduction resulting from monotherapy with either prazosin or clonidine occurs through different antisympathetic effects, suggesting that combined therapy might be useful in those unresponsive to either drug alone.

Prazosin as initial antihypertensive therapy: correlates of sympathetic function.

Abnormal sympathetic function has been proposed as a factor in the development of essential hypertension. If this is the case, prazosin hydrochloride, which works by a selective, peripheral, antisympathetic effect--postsynaptic alpha blockade--may have an advantage over other antihypertensive agents. In this study, blood pressure response and measures of sympathetic and baroreflex function were followed in 13 hypertensive patients. Prazosin alone significantly reduced standing and sitting diastolic blood pressures without affecting pulse rates, plasma catecholamines or baroreflex slopes in all patients. The addition of a thiazide diuretic in persons who did not achieve goal blood pressure on prazosin alone was generally successful in reducing blood pressure to desired levels, and increased both plasma renin activity and aldosterone concentrations. No significant relation was apparent between specific characteristics of sympathetic function and response to prazosin as initial therapy, although patients responding tended to have initially higher plasma norepinephrine concentrations.

Effect of transdermal clonidine on the endocrine responses to insulin-induced hypoglycemia in essential hypertension

Clonidine hydrochloride via the central nervous system lowers blood pressure, inhibits ACTH and catecholamine release, and stimulates growth hormone secretion. To evaluate the effect of this drug on the release of glucoregulatory hormones during hypoglycemia, we studied the responses to insulin‐induced hypoglycemia (0.1 units/kg) in 10 patients with mild essential hypertension before and after treatment for 16 weeks with transdermal clonidine. Clonidine significantly lowered blood pressure, basal plasma norepinephrine levels, and epinephrine and renin activity but did not affect basal growth hormone concentrations. Clonidine significantly reduced the norepinephrine and epinephrine responses to hypoglycemia (norepinephrine AUC from 207 ± 16 SE to 156 ± 25 nmol/L/min, epinephrine from 157 ± 28 to 99 ± 29 nmol/L/min; both p < 0.05) and increased the growth hormone response (AUC from 763 ± 148 ng/min/ml to 1164 ± 292 ng/min/ml; p < 0.05) but did not affect the Cortisol response or the magnitude or rate of glucose recovery from hypoglycemia. Thus transdermal clonidine has several effects on glucose counterregulatory hormones that do not significantly alter insulin sensitivity or impair recovery from hypoglycemia.

Diabetes and Hypertension: Clonidine Monotherapy

Hypertension and diabetes mellitus frequently occur together. Half of all diabetics may eventually become hypertensive (Christlieb 1973), most developing so-called essential hypertension partly related to the frequent occurrence of obesity in the diabetic population, and also perhaps reflecting relative expansion of the extracellular fluid space (de Chatel et al. 1977) or poor compliance of large vessels in turn producing high systolic blood pressures. Usually, however, hypertension in diabetics is related to the development of diabetic nephropathy and the characteristic glomerular lesion. Other possible mechanisms are large vessel atherosclerosis leading to renovascular hypertension (Muichoodappa et al. 1979) and abnormalities in diabetic neural function (and perhaps the baroreflex) leading to a rise in supine blood pressure.