Racial differences in the renal response to blood pressure lowering during chronic angiotensin-converting enzyme inhibition: a prospective double-blind randomized comparison of fosinopril and lisinopril in older hypertensive patients with chronic renal insufficiency.

This study was undertaken to compare the effects of chronic angiotensin-converting enzyme (ACE) inhibition on blood pressure (BP) and renal hemodynamics in older black and nonblack hypertensive patients with chronic renal insufficiency. A multicenter, placebo lead-in double-blind, parallel group study was performed to compare the antihypertensive efficacy and renal hemodynamic response to the once-daily ACE inhibitor fosinopril (n = 14) and lisinopril (n = 13) over a 22-week period. The study goal was to lower diastolic blood pressure (DBP) to 90 mm Hg or less. Furosemide was added after 6 weeks if blood pressure goal was not achieved. At outpatient clinics at university medical centers, 27 older hypertensive patients (> or = 45 years; 12 blacks, 15 nonblacks; 19 male, eight female) with DBP of 95 mm Hg or higher and 4-hour creatinine clearance 20 to 70 mL/min/1.73 m2 were studied. Changes (delta) from baseline in BP, glomerular filtration rate (GFR), and renal plasma flow (RPF) were measured. Mean systolic blood pressure (SBP) and DBP decreased significantly and to a similar extent in randomized groups: fosinopril (mean +/- SEM) delta DBP at 6 weeks was -13 +/- 2 (P < 0.0001; 95% CI, -16 to -9) and at 22 weeks was -12 +/- 2 (P < 0.0001; 95% CI, -16 to -9); lisinopril delta DBP at 6 weeks was -14 +/- 6 (P < 0.0001; 95% CI, -10 to -18) and at 22 weeks was -16 +/- 2 (P < 0.0001; 95% CI, -12 to -21). GFR and RPF did not change significantly in either group. BP was significantly reduced and to a similar extent in blacks and nonblacks: for blacks, delta DBP at 6 weeks was -11 +/- 3 (P < 0.05; 95% CI, -0.01 to -9) and at 22 weeks was -16 +/- 2 (P < 0.0001; 95% CI, -11 to -20); for nonblacks, delta DBP at 6 weeks was -14 +/- 1 (P < 0.0001; 95% CI, -12 to -17) and at 22 weeks was -12 +/- 2 (P < 0.0001; 95% CI, -16 to -8). Eight patients (five blacks and three nonblacks) required an addition of furosemide after 6 weeks to reach the DBP goal of < or = 90 mm Hg at 22 weeks. GFR was not significantly altered for either racial group at 6 weeks; however, at 22 weeks; however, at 22 weeks, GFR decreased significantly in blacks (delta GFR, -16 +/- 5; P < 0.006; 95% CI, -26 to -5) and tended to increase in nonblacks (delta GFR, 7 +/- 6; P > 0.25). delta GFR correlated directly with the delta RPF (delta GFR = 0.0611* delta RPF -2.35 +; r = 0.68; P < 0.003). There was no correlation between delta MAP and delta GFR or delta RPF in blacks or nonblacks. We conclude that chronic ACE inhibition with fosinopril and lisinopril alone or in combination with furosemide lowers BP in older blacks and nonblacks with hypertension and chronic renal insufficiency. Racial differences in the renal hemodynamic response to chronic ACE inhibition were noted and appear to be independent of diuretic use and the magnitude of BP lowering.

Effect of ramipril on blood pressure and protein excretion rate in normotensive nondiabetic patients with proteinuria.

Angiotensin-converting enzyme inhibitors reduce proteinuria in both normotensive and hypertensive patients with proteinuric renal disease. However, the mechanism of the antiproteinuric effect has not been clarified. We performed a prospective, double-blind, placebo-controlled, randomized crossover trial to test the hypothesis that the antiproteinuric effect of ramipril was due to an improvement in glomerular permselectivity independent of blood pressure and glomerular filtration rate. The effect of low-dose (1.25 mg/d) and high-dose (5 mg/d) ramipril was assessed in 15 normotensive nondiabetic patients with proteinuria (> 150 mg/d). The study was divided into four 12-week periods: placebo, high- or low-dose ramipril, crossover to low- or high-dose ramipril, and placebo. Blood pressure, glomerular filtration rate, renal plasma flow rate, urinary protein excretion rate, and plasma angiotensin II levels were measured at the end of each period. Mean arterial pressure, urine protein to creatinine ratio, and albumin excretion rate decreased significantly during low- and high-dose ramipril. Glomerular filtration rate and renal plasma flow rate were not changed significantly. Plasma angiotensin II levels decreased with both low- and high-dose ramipril. There were no episodes of hypotension and only one subject developed cough during ramipril that did not require discontinuation of the study drug. In conclusion, administration of ramipril in both low and high doses lowered blood pressure and reduced proteinuria in this cohort of normotensive patients with a variety of proteinuric renal diseases. The antiproteinuric effect of ramipril is probably mediated by a reduction in glomerular capillary pressure.

"Strict" blood pressure control and progression of renal disease in hypertensive nephrosclerosis.

Hypertensive nephrosclerosis is a progressive renal disease and the leading cause of end-stage renal disease (ESRD) in blacks in the United States. It is generally believed that hypertensive renal injury is responsible for progressive renal failure; however, it is not known whether pharmacologic lowering of blood pressure to any level prevents progression of renal disease. Accordingly, we performed a long-term prospective randomized trial to determine whether "strict" [diastolic blood pressure (DBP) 65 to 80 mm Hg] versus "conventional" (DBP 85 to 95 mm Hg) blood pressure control is associated with a slower rate of decline in glomerular filtration rate. Eighty-seven non-diabetic patients (age 25 to 73; 68 black, 58 male) with long-standing hypertension (DBP > or = 95 mm Hg), chronic renal insufficiency (GFR < or = 70 m/min/1.73 m2) and a normal urine sediment were studied. DBP was pharmacologically lowered to < or = 80 mm Hg (3 of 4 consecutive measurements at 1 to 4 weeks intervals) after which patients were randomized. DBP and GFR (renal clearance of 125I-iothalamate) were measured at baseline, at three months and every six months post-randomization. The rate of decline in GFR (GFR slope, in ml/min/1.73 m2/year), estimated by the method of maximum likelihood in a mixed effects model, was the primary outcome variable. In a secondary analysis, 50% reduction in GFR (or a doubling of serum creatinine) from baseline, ESRD and death were combined.(ABSTRACT TRUNCATED AT 250 WORDS)

VH gene structure predicts a large potential anti-insulin repertoire.

The majority of insulin antibodies derived from immunization are IgG antibodies that cross-react extensively with the autologous hormone. To examine the relationship between VH genes expressed by such self-reactive antibodies and their germline (non-rearranged) counterparts, we used the polymerase chain reaction (PCR) to amplify and isolate the germline progenitors of anti-insulin VH genes derived from BALB/c mice immunized with beef or human insulin. Results indicate that two anti-insulin mAbs (123 and 124) express VH genes which arise from a small subset of the J558 gene family and are highly homologous to the VH gene used by the murine CD5 + B-cell tumor, BCL1. The anti-insulin IgG mAb 127 belongs to the VH-VIII (Vgam 3.2) family and the amplification and isolation of germline VH genes from this small family precisely identified only two somatic mutation events in the CDRH2 of mAb 127. Another anti-insulin mAb, 133, also shows two replacement substitutions in the CDRHs when compared to the germline encoded anti-dextran antibody 19.1.2. These findings indicate that the IgG response to this small self-protein uses multiple VH genes which are largely germline encoded with only a low level of somatic mutation in their CDRHs. Additionally, analysis of N-segment additions in CDRH3s indicates anti-insulin B cells may originate from both early (fetal) and adult repertoires. These data are consistent with the concept that the mechanisms of clonal anergy or deletion do not regulate anti-insulin B cells and indicate that there is a large potential VH gene repertoire for insulin.

Extrapulmonary thoracic disease caused by Blastomyces dermatitidis.

A case of blastomycosis is reported involving the mediastinum and compromising the plexus brachialis. The pathology, pathophysiology, and treatment of this patient and of a previously reported patient are discussed and compared with the characteristics of extrapulmonary thoracic disease caused by histoplasmosis. Because of the favorable response of these patients to prolonged antifungal therapy, blastomycosis should be considered in the differential diagnosis of invasive extrapulmonary thoracic disease.

Treatment of hypertension in nondiabetic renal disease.

Over the past two decades the incidence of stroke and myocardial infarction in hypertensive populations has decreased, yet the incidence of end-stage renal disease attributed to hypertension has increased. This apparent paradox has raised questions about the adequacy of blood pressure control in hypertensive patients with renal disease. Chronic renal failure is commonly associated with hypertension, and is often severe and difficult to control, particularly in patients with hypertensive nephrosclerosis. The optimal level of blood pressure control in these patients has not been established. Long-term diastolic blood pressure control to a level lower than 90 mm Hg is associated with stable or improving renal function in hypertensive nephrosclerosis and with slowing of the deterioration in renal function from other causes of renal failure. Moreover, recent studies indicate that when blood pressure control is achieved and maintained at a level of about 130/86 mm Hg (systolic/diastolic), deterioration in renal function can be halted even in black patients with hypertensive nephrosclerosis. Therefore, in hypertensive nephrosclerosis we attempt to control diastolic blood pressure at 80 to 85 mm Hg. Newer antihypertensive agents such as calcium channel blockers and angiotensin-converting enzyme inhibitors contribute to lowering blood pressure and preserving renal function. However, they have yet to be proven superior to conventional agents in double-blind randomized clinical trials in humans with hypertensive nephrosclerosis. Importantly, minoxidil is still relied on for aggressive control of blood pressure in many patients with hypertensive nephrosclerosis.

Hyperfiltration and conservation of renal function in hypertensive nephrosclerosis patients.

Renal glomerular hyperfiltration has been proposed as an important contributing factor to the progression of hypertensive nephrosclerosis in rats with reduced renal mass. However, no clinical studies have assessed the role of glomerular hyperfiltration in the pathogenesis of hypertensive nephrosclerosis in humans. In a prospective, randomized, long-term blood pressure control study with up to 3 years follow-up, we showed that good blood pressure control with a mean diastolic blood pressure < or = 95 mm Hg preceded by a 2- to 4-month period of diastolic blood pressure < or = 80 mm Hg improved renal function in hypertensive nephrosclerosis patients. Patients treated with minoxidil, an angiotensin-converting enzyme inhibitor (enalapril), or a calcium entry blocker (nifedipine) had improvement in renal function, as indicated by a positive slope of the reciprocal serum-creatine concentration versus time and an increment in glomerular filtration rate. These results suggested that improvement in renal function occurred with these major types of antihypertensive drug treatment. To assess the renal hemodynamics of minoxidil, enalapril, and nifedipine, eight patients with hypertensive nephrosclerosis were admitted to the General Clinical Research Center for renal clearance studies on each drug while ingesting a fixed-calorie, 12% protein, 40% fat, and 100 mEq Na/d diet. Mean blood pressure, effective renal plasma flow, and renal vascular resistance did not change during the three phases of treatment. However, minoxidil treatment increased the glomerular filtration rate by 48% versus enalapril and by 79% versus nifedipine. Since minoxidil treatment improves renal function while causing a relative hyperfiltration, glomerular hyperfiltration per se is an unlikely mechanism for the progression of hypertensive nephrosclerosis in humans.

Reversible renal insufficiency due to angiotensin converting enzyme inhibitors in hypertensive nephrosclerosis.

OBJECTIVE: To review the incidence of reversible renal insufficiency in patients with hypertensive nephrosclerosis undergoing antihypertensive therapy. DESIGN: Retrospective analysis of 73 patients in a long-term blood pressure control study that compared the effects of an angiotensin converting enzyme (ACE) inhibitor plus conventional antihypertensive agents compared with placebo plus antihypertensive agents. SETTING: Hospital-based outpatient treatment center. INTERVENTIONS: Patients were divided into group 1, which received enalapril plus conventional antihypertensives, and group 2, which received placebo plus conventional antihypertensives. MEASUREMENTS: Blood pressure and serum creatinine levels were measured, and imaging studies of the main renal arteries were done. MAIN RESULTS: In group 1, eight of 42 patients (19%, 95% CI, 9% to 34%) developed reversible renal insufficiency, defined as an unexpected increase in serum creatinine of 88 mumol/L or higher. Six episodes of reversible renal insufficiency occurred during July and August when temperatures were 32.2 degrees C to 37.8 degrees C (90 degrees F to 100 degrees F). Renal artery stenosis was excluded by renal arteriogram or ultrasonic duplex scanning. All eight group-1 patients had a significant decrease in mean arterial pressure below their baseline level during reversible renal insufficiency (mean change, -28 +/- 10 mm Hg, P less than 0.001). The increase in the serum creatinine level was inversely correlated with the decrease in the mean arterial pressure (r = -0.68, P less than 0.01). Reversible renal insufficiency was successfully managed by withdrawing or reducing enalapril as well as other antihypertensive agents. Subsequently, enalapril was tolerated by seven of the eight patients without recurrence of renal insufficiency. In contrast, none of 31 (CI, 0% to 11%) patients in group 2 developed reversible renal insufficiency despite the fact that both the incidence of decreases in mean arterial pressure in 6 of 31 patients (19%) and the magnitude of the decreases in mean arterial pressure (mean change, -33 +/- 16 mm Hg) were similar to those observed in group 1. CONCLUSIONS: Reversible renal insufficiency in hypertensive nephrosclerosis associated with ACE inhibitor therapy correlates with relative hypotension, is not dependent on renal artery stenosis, and can usually be managed by dose reduction.

Long-term improvement in renal function after short-term strict blood pressure control in hypertensive nephrosclerosis.

Seventy-nine hypertensive nephrosclerosis patients entered a prospective randomized single-blind study to 1) establish the pattern of decay of renal function in this population and the variability therein and 2) to determine if strict diastolic blood pressure (DBP) control (less than or equal to 80 mm Hg) is more effective than conventional levels (90-95 mm Hg) in conserving renal function. Because of unexpected significant improvement in renal function in patients from both groups, which changed the perspectives on the course of this disease as described herein, this report is being published before completion of the trial. The selection criteria were 1) serum creatinine concentration of 1.6-7.0 mg/dl, 2) glomerular filtration rate of less than 70 ml/min/1.73 m2, and 3) absence of diseases (other than hypertension) known to destroy renal function. Renal function was assessed by glomerular filtration rate [( 125I]iothalamate clearance) and serum creatinine concentration. Before randomization, DBP was aggressively treated to reduce it to less than 80 mm Hg. Twenty-two subjects (14 in the strict DBP control group and eight in the conventional DBP control group) have been enrolled in the study for 36 months. In contrast to results from previous studies in humans and rats, renal function improved in both patient groups. Thus, irrevocable progression of renal damage after onset of renal failure from high blood pressure does not necessarily occur, and in fact, long-term improvement of renal function resulted from the effects of the study itself.(ABSTRACT TRUNCATED AT 250 WORDS)

Pseudo renal artery stenosis (PRAS) syndrome.

During the course of a long-term, prospective, randomized study in 77 hypertensive nephrosclerosis patients, five patients developed evidence suggestive of renal artery stenosis. However, arteriography demonstrated patent renal arteries. The evidence suggestive of renal artery stenosis was: (1) converting-enzyme inhibitor (CEI)-induced renal dysfunction including marked and reversible increases in serum creatinine and urea concentrations, (2) minoxidil-induced hyperreninemia despite beta-adrenoceptor blockade and volume expansion, and (3) minoxidil-induced salt and water retention with diuretic resistant edema. Thus, the renal dysfunction induced by CEI in these patients with patent renal arteries is similar to the alterations occurring in patients having bilateral renal artery stenosis. The diuretic resistant edema and the beta-adrenoceptor blocker resistant high renin release are also functional alterations of renal artery stenosis. We suspect that the long-standing and usually severe hypertension in these patients has caused sufficient arteriolar hypertrophy or sclerosis to interfere with renal blood flow and to induce these functional lesions of renal artery stenosis. With widespread use of the new CEI agents in patients with renal disease, this syndrome suggestive of renal artery stenosis may be encountered in as many as 10% of hypertensive nephrosclerosis patients during long-term treatment with converting-enzyme inhibitors.

Side effects of vasodilator therapy.

Vasodilating antihypertensive drugs have in common the capacity to activate the peripheral sympathetic nervous system through the carotid sinus baroreceptor reflex mechanism, thereby increasing heart rate, renin release, and sodium and water retention. They differ in their tendencies to augment cardiac output and to relieve or precipitate cardiac failure and arrhythmias. Vasodilating antihypertensive drugs can produce an array of side effects and toxicity including headache, facial changes, hair growth, varying degrees of sodium and water retention, and rarely systemic lupus erythematosus and allergic reactions. Detailed knowledge of these effects is a prerequisite to skillful individualization of antihypertensive regimens.

Further studies on the hypernoradrenergic state of treated hypertensives: effect of captopril.

We investigated the effect of captopril on plasma norepinephrine concentration and blood pressure in two groups of hypertensive patients. One group consisted of five severely hypertensive patients rendered hypernoradrenergic by administration of a minoxidil-propranolol-diuretic regimen. The other group was ten untreated mildly hypertensive patients. Two hours after 12.5mg of captopril, blood pressure was lowered (p less than .05) in four of the five hypernoradrenergic patients from 180 +/- 8/102 +/- 8 to 132 +/- 7/77 +/- 8 mmHg. Chronic administration of 100-150mg of captopril tid caused no further blood pressure reduction. Precaptopril plasma norepinephrine concentration was 925 +/- 206 and two hours after the 12.5mg dose was 807 +/- 80 pg/ml. Three months later having advanced the dose to 300-450 mg/day it was lower (p less than .05) at 752 pg/ml. The acute blood pressure response correlated (r = -0.72, p less than .001) with the precaptopril plasma norepinephrine. Precaptopril blood pressure in the mild hypertensive patients was 146 +/- 4/98 +/- 1, after a 25-100mg dose it was 137 +/- 6/91 +/- 2 (diastolic p less than .05) and at two months with the same captopril dose bid it was 141 +/- 8/88 +/- 4 mmHg (diastolic p less than .01). Corresponding initial PNE was 425 +/- 72, two hours after captopril 405 +/- 47 and 310 +/- 63 pg/ml (p less than .05) with chronic administration. Thus, captopril lowers blood pressure in both hypernoradrenergic and eunoradrenergic hypertensive patients without increasing plasma norepinephrine suggesting some unique dampening effect of this drug on the sympathetic nervous system. Also, addition of captopril to triple therapy lowered blood pressure in proportion to plasma norepinephrine levels suggesting importance to its action on this sympathetic nervous system effector.

Clonidine and prazosin effects in hypernoradrenergic vasodilator-treated and beta-blocker-treated patients.

Our subjects were seven severely hypertensive patients with blood pressures (BPs) over 140/90 who were using minoxidil, propranolol, and diuretics. Clonidine followed by prazosin was added to their regimen on an outpatient basis to establish the dose-response for BP and catecholamines. Plasma renin activity (PRA), body weight, and renal function were measured. Clonidine was given in doses of 0.2, 0.4, 0.6, and 0.8 mg/day. Supine and standing systolic BP decreased at all dose levels of clonidine (P less than 0.01, P less than 0.05). Diastolic BP decreased in the standing position with doses of 0.4, 0.6, and 0.8 mg (P less than 0.01, P less than 0.05). Subjects were hypernoradrenergic initially with plasma norepinephrine (PNE) 895 +/- 122 pg/ml. PNE was suppressed by 0.2 to 0.8 mg clonidine (P less than 0.01) with near maximal suppression at 0.4 mg daily. Systolic BP correlated with PNE (r = 0.59, P less than 0.001). Supine and standing PRA decreased after 0.2 mg clonidine (P less than 0.05) but not after higher doses. Our findings suggest the antihypertensive action of clonidine is related to PNE suppression but not to that of PRA. Plasma epinephrine (PE), body weight, and renal function did not change. Prazosin was given after clonidine to the same patients in a dose range of 3 to 40 mg/day. With doses of 6 to 40 mg, systolic and diastolic and supine and standing BP fell (P less than 0.001, P less than 0.01). PNE remained elevated throughout all dose levels and did not correlate with BP. Weight rose with prazosin (P less than 0.02) but PE, PRA, and renal function did not change. Hence, clonidine and prazosin induced additional lowering of BP but had different effects of PNE and weight.

Dose-response of clonidine on plasma catecholamines in the hypernoradrenergic state associated with vasodilator beta-blocker therapy.

Six patients receiving minoxidil, propranolol, and diuretics had clonidine added in increasing dosage. Five patients received 0.2-0.8 mg/day clonidine and one patient 0.2-0.6 mg. Plasma catecholamines, renin activity, blood pressure, and serum creatinine were measured at each dose level. The patients had a hypernoradrenergic state prior to clonidine [mean +/- SE plasma norepinephrine (PNE), 924 +/- 141 pg/ml]. Administration of clonidine, 0.2-0.8 mg/day, lowered supine PNE (p less than 0.01, p less than 0.02), and clonidine, 0.4-0.8 mg/day, lowered standing PNE (p less than 0.01, p less than 0.02). Maximal suppression of PNE occurred with 0.4 mg/day. Systolic blood pressure correlated with supine PNE (r = 0.055, p less than 0.05) at 0.2-0.8 mg/day clonidine, and standing PNE correlated (r = 0.72, p less than 0.01) at 0.2-0.6 mg/day. Plasma epinephrine concentration, plasma renin activity (PRA), and serum creatinine did not show any significant change. PRA did not correlate with blood pressure changes. Plasma clonidine concentration correlated reciprocally with the change in PNE (r = -0.59, p less than 0.01). These findings indicate that clonidine can return elevated PNE to normal levels in the vasodilator beta-blocker-treated patient and thus remove this abnormality as a contributing factor to pathogenetic mechanisms.

Renal function during long-term treatment of hypertension with minoxidil: comparison of benign and malignant hypertension.

We examined the effect of long-term blood pressure control on renal function in 41 patients with refractory hypertension by using minoxidil, sympathetic suppressants, and diuretics continuously for 6 months to 7 1/2 years. In 15 of 32 patients with benign hypertension, the serum creatinine concentration increased by more than 1 mg/dL, with nine of 15 requiring hemodialysis. Analysis of 1/serum creatinine versus time plots indicated that use of minoxidil delayed the onset of end-stage renal failure in some patients for up to 6 years. In the remaining 17 patients with benign hypertension, renal function remained stable with no decreases greater than 2 mg/dL. Four of nine patients presenting with malignant hypertension had marked and sustained improvement in renal function, although three initially required hemodialysis. The mean serum creatinine concentration in these four patients fell from 9.7 to 2.9 mg/dL. Thus, impressive renal functional improvement may occur with minoxidil use in some patients with malignant hypertension.

Renal function in long-term minoxidil-treated patients.

Renal function was monitored in 20 previously refractory hypertensive patients treated for 2--7 years with minoxidil, sympathetic suppressants, and diuretics. Serum creatinine concentration increased by more than 1 mg/dl in 9 of the 20 patients. In 4 of the 9 patients, renal disease progressed to require hemodialysis. Eleven patients had no progression of renal disease (creatinine increased less than or equal to 1 mg/dl). Three of the 11 had had malignant hypertension with renal failure which was reversed during this triple therapy. Neither the quality of blood pressure control nor the duration of minoxidil therapy correlated with increases in serum creatinine concentration. Plasma norepinephrine levels were higher (p less than 0.01) and plasma renin activity lower (p less than 0.02) in the group with progression of renal disease. Serum creatinine at the time when neuroendocrine studies were done correlated with PNE (r = 0.51, p less than 0.05). Addition of clonidine to this triple regimen in 2 patients with advanced renal disease lowered plasma norepinephrine by 63 and 81%. These findings suggest that the high norepinephrine levels are due to excess release of norepinephrine rather than defective renal elimination of this catecholamine. Whether the elevated plasma norepinephrine contributes to or is a result of the underlying disease is not known.

The hypernoradrenergic state in vasodilator drug-treated hypertensive patients: effect of clonidine.

We studied 11 previously refractory hypertensive subjects who were treated with minoxidil, propranolol, and diuretics for 2--7 years. During this time 70 random blood samples were collected in the supine position and analyzed for plasma norepinephrine (PNE) and plasma renin activity (PRA). The mean PNE was 546 pg/ml (normal mean +/- SE, 173 +/- 10) and was reciprocally related to log PRA. To determine if this elevated PNE would respond to clonidine, 5 of the patients were admitted to the General Clinical Research Center for administration of placebo and later of clonidine (0.1 or 0.2 mg). A single dose of clonidine suppressed PNE (p less than 0.01) and lowered mean blood pressure (p less than 0.02) for 12 hr. The PRA was not altered significantly by clonidine. Thus, high PNE in these treated patients can be suppressed by clonidine, and this suppression of PNE and blood pressure occurs without alteration of PRA.

Drug interactions with saralasin.

Diuretic and vasodilator drugs alter the BP response to saralasin causing drug interactions. Saralasin-induced BP reduction is related directly to PRA and intravascular volume. Diuretic agents deplete intravascular volume and elevate PRA, enhancing saralasin hypotension. Vasodilating agents increase PRA and may induce angiotensin dependence of BP. Thus, with potent vasodilators, saralasin can induce hypotension. Rebound hypertension has been reported after saralasin infusion in several patients with accelerated or malignant hypertension. Theoretically, this BP elevation could be related to sustained release of renin resulting from disinhibition of an intrarenal angiotensin receptor inhibitory to renin release. Since propranolol can block saralasin-induced renin release, angiotensin and beta-blockers could constitute a beneficial drug interaction.

Long-term treatment of refractory hypertensive patients with minoxidil.

Twenty-nine hypertensive patients refractory to conventional medications were treated continuously with minoxidil, sympathetic suppressants, and diuretics for six months to five years (mean, 30 months). All had evidence of hypertensive end-organ damage before minoxidil therapy. Good blood pressure control was obtained in 21 (72%) of 29 patients when minoxidil was given in dosages up to 40 mg/day. No tolerance was found. In the remaining eight, good control was obtained in three when phenoxybenzamine therapy was added, and in one when clonidine therapy was added. Renal failure requiring hemodialysis developed in five of 29, one had temporary hemiparesis, and one had fatal cerebral hemorrhage. In the remainder, myocardial infarctions and strokes were effectively prevented. Patients receiving minoxidil and propranolol hydrochloride had elevated plasma norepinephrine levels while those receiving clonidine had normal plasma norepinephrine levels.

Clonidine and the vasodilating beta blocker antihypertensive drug interaction.

Because propranolol is contraindicated in some patients and since clonidine can decrease heart rate and renin release, clonidine was substituted for propranolol in 14 severely hypertensive minoxidil-treated outpatients. Clonidine induced weight loss which, since plasma concentrations were not suppressed, was not due to inhibition of release of antidiuretic hormone or renin. These endocrine interrelations were confirmed by later administration of clonidine to 4 of the subjects under controlled circumstances in our General Clinical Research Center. When substituted for propranolol, clonidine controlled blood pressure and heart rate in 8 of the 9 outpatients whose blood pressure had been previously well controlled. Clonidine and propranolol had additive antihypertensive effects in the other 5 patients. Thus, clonidine can substitute for propranolol or when added to the propranolol-vasodilator combination supply an additional blood pressure-lowering effects. This substitution or addition results in an increase in side effects. In addition, clonidine has a diuretic action under these circumstances by an unknown mechanism.