Effect of indomethacin on blood pressure lowering by captopril and losartan in hypertensive patients.

NSAIDs are known to attenuate the effects of some antihypertensive medications. It is not known whether the new class of angiotensin II receptor antagonists is similarly affected. We conducted a multicenter study assessing the effect of indomethacin on the antihypertensive effects of losartan and captopril. After 4 weeks of placebo washout, hypertensive patients received 6 weeks of active antihypertensive therapy with either 50 mg losartan once daily (n=111) or 25 mg captopril twice daily for 1 week, which was increased to 50 mg twice daily for 5 weeks (n=105). This was followed by 1 week of concomitant therapy with indomethacin (75 mg daily). The primary outcome measure was the change in mean 24-hour ambulatory diastolic blood pressure after the addition of indomethacin. Both captopril and losartan significantly lowered ambulatory diastolic blood pressure (losartan -5.3 mm Hg, P:<0.001; captopril -5.6 mm Hg, P:<0.001) after 6 weeks of therapy. Indomethacin significantly attenuated the 24-hour ambulatory diastolic blood pressure for both losartan (2.2 mm Hg, P:<0.05) and captopril (2.7 mm Hg, P:<0.001) and also attenuated the effect of captopril on trough sitting diastolic blood pressure. Changes in daytime diastolic blood pressure (7:00 AM to 11:00 PM) were similar to the 24-hour response in both groups. Nighttime diastolic blood pressure (11:01 PM to 6:59 AM) was significantly attenuated in captopril-treated patients (2.0 mm Hg, P:<0.05), but losartan was unaffected (0.4 mm Hg). Thus, concurrent treatment with indomethacin similarly attenuates the 24-hour antihypertensive response to losartan and captopril.

Subtle glucocorticoid excess in patients with adrenal incidentaloma.

Incidentally discovered adrenal tumors (incidentalomas) are fairly common since the advent of noninvasive methods of imaging the abdomen. Patients with incidentaloma usually undergo screening for overproduction of glucocorticoids by measurement of basal steroid excretion. We describe an asymptomatic patient with an incidentaloma with normal basal steroid excretion whose only manifestation of subtle steroid overproduction was the failure of steroid excretion to be suppressed normally with dexamethasone. It appears tht the more careful the search for subtle evidence of steroid overproduction in patients with incidentaloma, the more common the finding; perhaps up to 50% of patients with incidentaloma have some subtle steroid overproduction. We review the literature on this subject, and evaluate the various possible approaches of how intensively to study steroid dynamics in patients with incidentaloma.

H(+)-stimulated release of prostaglandin E2 and cyclic adenosine 3',5'-monophosphoric acid and their relationship to bone resorption in neonatal mouse calvaria cultures.

The addition of protons to the medium of neonatal mouse calvaria cultures stimulated bone resorption and release of calcium into the medium. In addition, added protons significantly increased the release of prostaglandin E2 (PGE2) and cyclic adenosine 3',5'-monophosphoric acid (cAMP) from the bones. Indomethacin significantly inhibited the release of calcium, PGE2 and cAMP from proton-treated cultures. The positive control, parathyroid hormone (PTH)-treated cultures, also gave rise to bone resorption and calcium release into the medium. However, unlike the addition of protons, the addition of PTH did not stimulate PGE2 release nor did indomethacin inhibit calcium release from PTH-treated cultures. In addition, indomethacin only slightly inhibited cAMP release from PTH-treated cultures, as compared to the marked inhibition by indomethacin of cAMP release from proton-treated cultures. These findings indicate that bone resorption due to added protons is dependent on both PGE2 and cAMP production, whereas bone resorption due to PTH only involves cAMP production.

Biochemical markers of compliance in the Physicians' Health Study.

The Physicians' Health Study is a randomized, double-blind, placebo-controlled trial using a 2 x 2 factorial design to test the effects of low-dose aspirin on risk of cardiovascular disease and beta-carotene supplementation on the incidence of cancer. To evaluate self-reported compliance with assigned treatment, we measured serum thromboxane B2, which is decreased after aspirin use, and plasma beta-carotene in samples of study participants drawn from three geographic locations in three different time periods. Thromboxane B2 levels were markedly lower in those assigned to aspirin (median = 63.5 pg/mL) than in those given aspirin placebo (median = 3,600 pg/mL, P less than .0001). Similarly, those assigned to beta-carotene had significantly higher levels (median = 1,176 ng/mL) than those given placebo (median = 306 ng/mL, P less than .0001). In addition, there was a highly significant positive correlation between levels of these biochemical markers and the self-reports of compliance (r = 0.65 for thromboxane B2 and r = 0.69 for beta-carotene, P less than .0001). These findings support the validity of the self-reported compliance in the Physicians' Health Study.

A multicenter comparison of isradipine and prazosin for treatment of essential hypertension.

Isradipine is a dihydropyridine calcium-entry blocking agent with pronounced vasodilator activity and no significant cardiac effects at clinical doses, a desirable profile for an antihypertensive drug. Prazosin, a post-junctional alpha-adrenoceptor blocking agent, may produce a similar hemodynamic pattern. Therefore, we compared the effects of isradipine (2.5-10 mg bid) with those of prazosin (2-8 mg bid) in 83 patients with established essential hypertension, using a randomized, double-blind, parallel-group design. Patients received a placebo for 3-5 weeks, then either isradipine or prazosin over a 6-week titration period, followed by a 4-week plateau phase. During the plateau period, isradipine therapy lowered sitting blood pressure more effectively than did the administration of prazosin: Mean systolic BP fell 16.7 versus 8.1 mmHg (p less than 0.001) and mean diastolic BP was reduced 15.6 versus 12.6 mmHg (p less than 0.01). In the dosing range used (while also noting that prazosin is occasionally titrated up to doses of 30 mg qd), 83% of isradipine-treated patients had at least a 10 mmHg reduction in diastolic BP, compared with 64% of prazosin-treated patients (p = 0.05, FET). Tachyphylaxis did not occur with either drug. The rate of occurrence of side effects was similar in both treatment groups; the most common adverse event seen with isradipine was headache (20%) and with prazosin, dizziness (19%).

Effect of angiotensin II on collagen-induced platelet activation in normotensive subjects.

We examined the effect of angiotensin II (AII) on platelet activation in 15 normotensive volunteers. By measuring the initial phase of platelet aggregation on the optical density aggregation tracing and generation of thromboxane production, we demonstrated that AII enhances collagen-induced platelet activation. This enhancement in platelet activation is significantly greater when subjects are on a high salt than on a low salt diet. Furthermore, the increase in platelet activation parallels an increase in platelet AII receptor number. These parallel changes in platelet activation and platelet AII receptors provide a possible mechanism through which AII may affect platelet function.

Religious experience and public cult: The case of Mary Ann Van Hoof.

This study focuses on the first year (1950) of the apparitions of the Virgin Mary reported by Mary Ann Van Hoof of Necedah, Wisconsin. It argues that Van Hoof's experiences met not simply the needs of the community-at-large, but also helped the seer draw meaning from an emotionally-deprived and abusive childhood. The study concludes by suggesting that public serial apparitions are complex events that should be examined for the light they shed on the interaction between the seer's personal characteristics and experiences and the public events that take shape around those experiences.

Antihypertensive and hormonal effects of PN 200-110, a new calcium-channel blocker, in essential hypertension.

Twenty-four patients (aged 34-68), with mild to moderate essential hypertension, received 10 weeks of treatment with the new calcium-channel blocker PN 200-110. Eighty-six percent of the patients achieved goal blood pressure (i.e., sitting diastolic pressure less than or equal to 90 mmHg). The average reduction in sitting and standing systolic and diastolic blood pressure (-14 +/- 2/-15 +/- 1 mmHg, -14 +/- 3/-13 +/- 2 mmHg, respectively) was highly significant (p less than 0.001). No reflex tachycardia (sitting pulse 1 +/- 2 bpm; standing pulse 3 +/- 2 bpm) or weight change (-0.3 +/- 0.9 pounds) accompanied the hypotensive response. Although the fall in blood pressure was accompanied by a small but significant increment in plasma renin activity (0.5 +/- 0.2 ng/ml/hr [p less than 0.05]), no significant changes in plasma angiotensin II, aldosterone, or prostaglandin E2-metabolite occurred. There was no significant correlation between the fall in blood pressure and baseline (pretreatment) or stimulated (posttreatment) levels of plasma renin activity, angiotensin II, aldosterone, or prostaglandin E2-metabolite.

Dissociation of the prostaglandin and renin angiotensin systems during captopril therapy for chronic congestive heart failure secondary to coronary artery disease.

Neurohumoral systems are activated as compensatory mechanisms in congestive heart failure (CHF). A close correlation has been reported between the renin angiotensin and prostaglandin systems in CHF. Furthermore, serum sodium concentration provided an excellent index of hormonal status. In this study, these relations were examined after acute and chronic blockade of renin angiotensin system with captopril. Eight patients with advanced CHF (New York Heart Association III or IV) were studied. Before captopril treatment, all hormone levels were elevated. Mean plasma renin activity was 24 +/- 7 ng Al/ml/hour, angiotensin concentration was 221 +/- 11 pg/ml and aldosterone concentration was 82 +/- 17 pg/ml. Plasma PGE2 metabolite was 1,425 +/- 321 pg/ml. A close correlation was observed between plasma angiotensin II and PGE2 metabolite levels (r = 0.7); inverse correlations existed between serum sodium concentration and PGE2 metabolite levels (r = -0.9) and with plasma renin activity (r = -0.6). Captopril therapy reduced the plasma angiotensin II level to 38 +/- 6 pg/ml and aldosterone concentration to 15 +/- 3 pg/ml, but did not affect plasma renin activity (31 +/- 10 ng Al/ml/hour) when measured in 1 week. Paradoxically, PGE2-metabolite levels increased further (to 3,031 +/- 346 pg/ml) despite blockade of the renin angiotensin system. Serum sodium concentration no longer correlated with hormone levels. These effects were sustained at 2 months of follow-up. Thus, captopril caused a dissociation between the renin angiotensin system and prostaglandin. The activation of prostaglandin is probably due to captopril's effect on prostaglandin biosynthesis and may contribute to captopril's sustained efficacy in CHF.

Endocrine and vascular responses in hypertensive patients to long-term treatment with diltiazem.

Forty patients (aged 28-66 years) with essential hypertension were randomized to 14 weeks of treatment with diltiazem or hydrochlorothiazide (HCTZ) in a double-blind, parallel study design. A significant reduction in supine body weight (-6.0 +/- 1.5 lb; p less than 0.001) and increase in pulse (+6 +/- 2 beats/min; p less than 0.001) occurred in HCTZ-treated patients. Patients receiving diltiazem had no change in weight, but did have a significant fall in pulse (-5 +/- 2 beats/min; p less than 0.05). The average reduction in supine systolic and diastolic blood pressures was comparable in both patient groups (-16 +/- 4/-11 +/- 2 mm Hg for HCTZ; -17 +/- 3/-12 +/- 1 for diltiazem). The reduction in blood pressure in HCTZ- and diltiazem-treated patients was not dependent on baseline plasma renin activity (PRA), but did not correlate significantly with changes in PRA and prostaglandin E2-metabolite (PGE2-M) (r = 0.51, p = 0.016). PRA increased +2.8 +/- 0.6 ng/ml/h (p less than 0.001) with HCTZ and +0.8 +/- 0.3 ng/ml/h (p less than 0.05) with diltiazem. PGE2-M also rose with both drugs (52 +/- 22 pg/ml for HCTZ; 63 +/- 36 pg/ml for diltiazem). Thus, diltiazem and HCTZ were similar in that the depressor response to each drug activated the renin-angiotensin system, which in turn was accompanied by increased production of PGE2-M.

Comparison of hydrochlorothiazide and sustained-release diltiazem for mild-to-moderate systemic hypertension.

The safety and efficacy of sustained-release diltiazem, 120 to 180 mg twice daily, was compared with those of hydrochlorothiazide, 25 to 50 mg twice daily, in 207 patients with mild-to-moderate hypertension (supine diastolic blood pressure [BP] 95 to 114 mm Hg) using a baseline, placebo, parallel-design study protocol. All patients received placebo for 2 to 4 weeks, followed by either study drug during the double-blind phase, titrated over 8 weeks to achieve a goal of supine diastolic BP reduction of at least 10 mm Hg and/or a diastolic BP of less than 90 mm Hg. Patients not achieving the treatment goal with either drug alone received the other drug in combination. Both drugs produced significant decreases in supine and upright BP throughout the 26-week study. The magnitude of decrease in mean supine diastolic BP was similar for both drugs as monotherapy at week 14 (-11.4 and -12.1 mm Hg, respectively). Hydrochlorothiazide produced significantly greater reductions at week 14 in mean supine systolic BP than sustained-release diltiazem (-19.5 and -12.7 mm Hg, respectively). The difference in mean supine diastolic BP reduction with the 2 drugs diminished when hydrochlorothiazide (50 mg/day) was compared with sustained-release diltiazem. The BP effects were sustained for 6 months with both drugs. The 2 drugs appeared to lower BP more in patients older than 60 years and more in black than in white patients. The combination of the 2 drugs decreased supine diastolic BP to goal levels in about 56% of the patients not achieving goal with either drug alone. Adverse effects were minimal with either drug alone and in combination, except for hypokalemia, which increased with thiazide alone and in combination.

The role of prostaglandins in mediating the effects of angiotensin converting enzyme inhibitors and other antihypertensive drugs.

This review considers the hypothesis that angiotensin converting enzyme (ACE) inhibitors and other antihypertensive drugs may reduce blood pressure by altering the balance of vasoconstrictor and vasodilator hormones. Most cases of essential hypertension are characterized by increased vascular resistance. Since vascular resistance can be viewed as a net balance of offsetting vasoconstrictor and vasodilator neurohumoral forces, and since angiotensin II and norepinephrine can stimulate the synthesis of vasodilator prostaglandins that can in turn counteract peripheral vasoconstriction, we measured changes in vasoconstrictor (angiotensin II) and vasodilator (PGE2) hormones after giving different antihypertensive drugs. We found that the sulfhydryl containing converting enzyme inhibitor captopril increased vasodilator prostaglandin production (PGE2-metabolite) both acutely and chronically. This increase in PGE2-metabolite was not seen with the non-sulfhydryl converting enzyme inhibitor, enalapril.

Effect of age on calcium release from mouse calvaria in tissue culture.

The effect of age on calcium release in organ culture was studied using calvaria from 5-, 14-, 30-, and 75-day-old mice. The results demonstrated a different and characteristic calcium release pattern over the 14-day culture period for untreated calvaria of different ages. Since calcium release in all cultures was abolished by procedures such as boiling, multiple freezing and thawing, maintaining cultures in an oxygen-free gas phase, or maintaining cultures in a non-nutritive medium, it was concluded that the calcium release from older calvaria was due to a cell-mediated process. Histological observations demonstrating the presence of Howship's lacunae and active osteoclastic resorption confirmed that calcium release from older calvaria was due to an active bone resorption process. Parathyroid hormone did not substantially alter the general pattern of calcium release exhibited by different aged calvaria. However, it tended to exaggerate the magnitude of the response. Indomethacin and dexamethasone inhibited calcium release from untreated 5- and 75-day-old calvaria suggesting that prostaglandin biosynthesis was involved in the calcium release process. Direct measurements of PGE2 and PGI2 released into the culture medium gave results consistent with this hypothesis, although it is conceivable that indomethacin and dexamethasone might have influenced calcium release by other mechanisms.

A randomized trial of the effect of vitamin E on plasma prostacyclin (6-keto-PGF1 alpha) levels in healthy adults.

We conducted a randomized, placebo-controlled double blind trial of the effect of vitamin E (800 IU/day) on plasma prostacyclin levels. After drawing baseline blood samples, 30 healthy adults were randomly assigned to vitamin E or placebo. After eight weeks, we again collected blood and assayed the plasma for 6-keto-PGF1 alpha, the principal stable degradation product of prostacyclin. Mean levels of 6-keto-PGF1 alpha in those patients who received placebo was essentially unchanged, 27 pg/ml at baseline and 29 pg/ml at 8 weeks. The mean level of those patients on vitamin E declined dramatically, from 29 to 13 pg/ml. The mean net difference due to vitamin E, -18 pg/ml (95% confidence limits from -32 to -3), was statistically significant, p = .02. It is not clear whether this effect is restricted to prostacyclin or if vitamin E exerts a similar tendency on other arachidonic acid derived products.

Prostaglandin levels in human vitreous.

Vitreous samples were obtained from 41 eyes undergoing vitrectomy, and radioimmunoassays were performed to measure concentrations of the prostaglandins PGE2, PGF2 alpha, prostacyclin, and thromboxane. Presumably physiological levels (approximately 100 picograms/ml) were found in vitreous from eyes undergoing cataract extraction. Eyes with vitreous haemorrhage, retinal detachment, or cystoid macular oedema had similarly low levels. Vitreous prostaglandins were mildly elevated in trauma and endophthalmitis and markedly elevated in aphakic bullous keratopathy. The role prostaglandins may play in cystoid macular oedema is reviewed.

Production of prostaglandins by dispersed cells and fragments from bovine parathyroid glands.

We studied the production of prostaglandins by fragments and dispersed cells from bovine parathyroid glands. Fragments released 138 +/- 19 (SE), 132 +/- 21, 4.3 +/- 0.5, and 13 +/- 6.6 pg/mg/h of 6-keto-PGF1 alpha, PGF2 alpha, PGE2, and thromboxane B2, respectively (n = 7 - 26), while dispersed cells released 414 +/- 110, 22 +/- 7.3, 27 +/- 3.8, and 29 +/- 11 pg/10(6) cells/h, respectively, of the same compounds (n = 6 - 25). Indomethacin (1 microgram/ml) inhibited the release of 6-keto-PGF1 alpha by 80-90% in fragments and cells, while mellitin stimulated release of this prostaglandin, suggesting de novo synthesis of prostaglandins in these preparations. Calcium stimulated production of 6-keto-PGF1 alpha by 1.3-fold in cells and 2.6-fold in fragments and also enhanced production of PGF2 alpha by 1.9-fold in fragments. Isoproterenol, on the other hand, had no effect on production of 6-keto-PGF1 alpha in either preparation. These results demonstrate that parathyroid tissue as well as parathyroid cells per se produce a variety of prostaglandins. We have previously shown that PGE2 and PGF2 alpha modulate cAMP accumulation and PTH release in dispersed bovine parathyroid cells. The role of the endogenous production of prostaglandins by the parathyroid gland in the acute or chronic regulation of parathyroid function, however, remains to be determined.

Prostaglandins in severe congestive heart failure. Relation to activation of the renin--angiotensin system and hyponatremia.

To determine whether prostaglandins are involved in circulatory homeostasis in congestive heart failure, we measured plasma levels of the metabolites of vasodilator prostaglandins I2 and E2 in 15 patients with severe chronic heart failure. Mean circulating levels of both metabolites were 3 to 10 times higher than those in normal subjects. Plasma levels of both metabolites correlated directly with plasma renin activity and plasma angiotensin II concentrations (r = 0.64 and 0.84, respectively). Individual serum sodium concentrations were inversely correlated with levels of prostaglandin E2 metabolites (r = -0.92, P less than 0.001) and plasma renin activity (r = -0.69, P less than 0.02). Of 23 patients with severe heart failure challenged with indomethacin (an inhibitor of prostaglandin synthesis), the 9 with hyponatremia had significant decreases in the cardiac index (1.99 +/- 0.12 to 1.72 +/- 0.13 liters per minute per square meter of body-surface area, P less than 0.001) and significant increases in the pulmonary capillary wedge pressure (17.4 +/- 2.0 to 24.0 +/- 1.9 mm Hg, P less than 0.001) and systemic vascular resistance (1882 +/- 239 to 2488 +/- 315 dyn x sec x cm-5, P less than 0.001), whereas the 14 patients with a normal serum sodium concentration had no significant hemodynamic changes. We conclude that both vasoconstrictor (renin-angiotensin) and vasodilator (prostaglandin) mechanisms are operative in patients with heart failure complicated by hyponatremia and that these mechanisms interact to modulate circulatory homeostasis.