Stephen L. Swartz

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.

Captopril-induced Changes in Prostaglandin Production: RELATIONSHIP TO VASCULAR RESPONSES IN NORMAL MAN

Captopril is a potent hypotensive agent whose efficacy has hitherto been attributed to its ability to alter either angiotensin II formation or kinin degradation. Our purpose was to examine captoprils acute effect on prostaglandin production, because changes in neither the renin-angiotensin nor the kallikrein-kinin systems appear adequate to account for the fall in arterial pressure. The plasma levels of angiotensin II, kinins, and prostaglandins were determined in response to increasing doses (5, 12.5, and 25 mg) of captopril and these responses were compared with the change in arterial pressure observed in nine supine normal male subjects studied on both a high (200 meq) and low (10 meq) sodium intake.Captopril significantly (P < 0.01) increased the levels of the 13,14-dihydro-15-keto metabolite of prostaglandin E(2) (PGE(2)-M), a potent vasodilator, with similar responses being observed on both a high and a low sodium intake. No significant changes in the plasma levels of 6-keto-prostaglandin F (1)alpha, or thromboxane B(2), the stable products of prostacyclin and thromboxane A(2), respectively, occurred. The depressor response to captopril correlated with the change in PGE(2)-M (r = 0.52, t = 5.44, P < 0.0001). On the other hand, although significant (P < 0.02) decrements in angiotensin II and increments in plasma kinins accompanied the hypotensive response in sodium-restricted subjects, in sodium-loaded subjects where the renin-angiotensin system was suppressed, no change in angiotensin II, and only a modest change in kinins was noted, even though significant (P < 0.01) decrements in diastolic blood pressure occurred (-10+/-2 mm Hg).Thus, changes in depressor prostaglandin production can better account for the hypotensive response to captopril, thereby extending to yet another vasoactive system an influence by this class of drugs and providing a new approach to dissecting the abnormality in the control of vascular tone in patients with hypertension.

Contribution of prostaglandins to the antihypertensive action of captopril in essential hypertension.

SUMMARY To determine whether prostaglandins contribute to the depressor response to the converting enzyme inhibitor, captopril, we measured the plasma prostaglandln levels by radioimmunoassay before and after captopril administration, and then examined the effect of prostaglandin synthetase inhibition on captoprils antihypertensive effect. When a single oral captopril dose (25-100 mg) was given to 31 sodium-restricted patients with essential hypertension, the levels of the stable transformation product of prostacyclin remained immeasurable and that of thromboxane A, did not change, while the metabolite of PGE, (PGE-M) increased by 53% (34 ± 4 pg/ml pre-captopril, 52 ± 5 pg/ral after; p < 0.001). As expected, blood pressure (BP) and angiotensin II (AH) levels fell, and kinin levels rose (all changesp < 0.001). We then blocked prostaglandin synthesis in 18 of these subjects for 24 hours with either indomethacin (n = 10) or aspirin (n = 8) before repeating the captopril dose, to assess the importance of these PGE-M increments. The PGE-M responses to captopril were effectively blocked in nine of 10 subjects receiving indomethacin and four of eight receiving aspirin. In these 13 patients, the depressor response to captopril was significantly blunted (− 20 ± 3 mm Hg pre-synthetase inhibition vs − 13 ± 2 mm Hg post; p < 0.05). When these agents did not block the PGE-M response to captopril, the BP response was also unchanged (-15 ± 4 mm Hg pre, −18 ± 5 mm Hg post). Neither indomethacin nor aspirin changed the AH or kinin responses to captopril. We conclude that the prostaglandins may be important mediators of captoprils antihypertensive effect in the sodium-restricted state.

Converting enzyme inhibition in essential hypertension: the hypotensive response does not reflect only reduced angiotensin II formation.

SUMMARY To determine the relative importance of hormonal factors in mediating the hypotensive response to converting enzyme inhibition (CEI), plasma renin activity (PRA), angiotensin II, and bradykinin responses to SQ20,881 were measured in 20 supine patients with essential hypertension in balance on a 10 mEq sodium diet. Patients were divided into two groups according to their diastolic blood pressure response: responders had a decrement in diastolic pressure which exceeded 9 mm Hg, toe upper value of the 95% confidence limits for normotensive patients studied under similar conditions; nonresponders did not. Compared to the nonresponders, responders not only had a higher control PRA (8.7 ± 1.7 ng/ml/hr vs4.8 ± 2.1, p < 0.05)and larger decrement in plasma angiotensin II (18.7 ± 4.9 pg/ml vs 3.2 ± 1.7, p < 0.01), but also had a higher control bradykinin (3 2 ± 0.7 ng/ml vs 1.1 ± 0.2, p < 0.05) and larger increment in bradykinin (4.5 ± 13 ng/ml vs 1.0 ± 0.4, p < 0.05) following SQ20.881. Because SQ20.881 altered both angiotensin II and bradykinin concentrations, we assessed the contribution of blockade of angiotensin II formation by administering angiotensin II infusions to seven responders during converting enzyme blockade, with the angiotensin II dose adjusted to restore diastolic pressure to control levels. The plasma angiotensin II level required to return blood pressure to control was 45 ± 15 pg/ml higher than the control plasma angiotensin II level (p < 0.01), suggesting that some other factors), perhaps bradykinin, are also responsible for the hypotensive response to converting enzyme inhibition.

Corticosteroids: Clinical Pharmacology and Therapeutic Use

SummaryThe widespread use of corticosteroids in clinical practice emphasises the need for a thorough understanding of their metabolic effects. In general, the actions of corticosteroids on carbohydrate, protein, and lipid metabolism result in increased hepatic capacity for gluconeogenesis and enhanced catabolic actions upon muscle, skin, lymphoid, adipose and connective tissues. Because of the morbidity associated with steroid therapy, the clinician must carefully consider in each case the gains that can reasonably be expected from corticosteroid therapy versus the inevitable undesirable side effects of prolonged therapy. Thus, it is important to remember that the enhanced anti-inflammatory activity of the various synthetic analogues of cortisol is not dissociated from the expected catabolic actions of glucocorticoid hormones.Replacement therapy with physiological doses of cortisol in primary or secondary adrenal insufficiency is intended to simulate the normal daily secretion of cortisol. Short term, high dose suppressive glucocorticoid therapy is indicated in the treatment of medical emergencies such as necrotising vasculitis, status asthmaticus and anaphylactic shock. With improvement of the underlying disorder, the steroid dosage can be rapidly tapered and then discontinued over a 2 to 3 day period. Long term, high dose suppressive therapy is often commonly used to treat certain diseases (see sections 4.7.2 and 4.7.3). In this setting, suppression of the hypothalamic-pituitary-adrenal axis may persist for as long as 9 to 12 months following steroid withdrawal if steroid doses are administered in the supraphysiological range for longer than 2 weeks. In general, higher doses, longer duration of usage, and frequent daily administration are all correlated with the severity of pituitary ACTH suppression.When steroid therapy is to be withdrawn, gradual tapering of the dosage is necessary; the steroid dosage should also be given as a single morning dose if possible. Rapid or total withdrawal of the steroid therapy may be associated with exacerbation of the underlying disease or with a steroid withdrawal syndrome. An additional important point to remember in any withdrawal programme is that the steroid dosage should be appropriately increased for an exacerbation of the underlying disease or for intercurrent major stress. Alternate day therapy is recommended as a steroid maintenance programme for patients requiring high dose glucocorticoid therapy over a prolonged period of time. Thus, it is usually employed to maintain a therapeutic benefit which had previously been established by daily steroid treatment.Complications resulting from corticosteroid therapy include: (1) proximal muscle weakness; (2) osteopenia; (3) unmasking of latent diabetes mellitus; (4) sodium retention and / or elevation of mean arterial blood pressure; (5) adverse psychiatric reactions; (6) development of glaucoma; and (7) reactivation of latent infections (such as tuberculosis).

Angiotensin-Converting Enzyme Inhibition and Prostaglandins

To determine whether prostaglandins contribute to the depressor response of angiotensin-converting enzyme inhibitors, plasma prostaglandin levels were measured by radioimmunoassay in normo- and hypertensive subjects on both sodium-restricted and sodium-loaded diets before and after captopril administration. On the sodium-restricted diet, the hypotensive response to captopril was accompanied by significant increments in the metabolite of prostaglandin E2 (PGE2-M) and bradykinin and by significant decrements in angiotensin II. The high sodium diet suppressed the response of the renin-angiotensin and kinin systems to captopril but the hypotensive response persisted. Furthermore, the decrease in blood pressure correlated significantly with increments in prostaglandin E2-metabolite. Prostaglandin synthesis was then inhibited in the sodium-restricted hypertensive patients by pretreatment with indomethacin. This maneuver completely eliminated the captopril-induced prostaglandin E2-metabolite increment without changing bradykinin or angiotensin II responses but significantly attenuating the hypotensive response. Finally, when patients were studied on a high sodium intake, similar effects were observed except now indomethacin completely abolished the blood pressure response to captopril. These studies therefore support the hypothesis that increased production of vasodilator prostaglandins in a major mediator of the hypotensive response to captopril. Whether the change in prostaglandin release is a direct effect of the drug or secondary to increased kinin levels is uncertain.

Increased glomerular filtration rate after converting-enzyme inhibition in essential hypertension.

To test the influence of an inhibitor of angiotensin-converting enzyme, teprotide (SQ 20881), we administered it to seven patients with essential hypertension and normal renal function and nine with an unequivocal reduction in creatinine clearance, caused by bilateral renal-artery stenosis in two and by essential hypertension in seven. Despite the fall in blood pressure (112.7 +/- 4.5 to 100.3 +/- 3.9 mm Hg, mean +/- S.E.M., P less than 0.01), there were prompt increases in both creatinine clearance (95.9 +/- 10.5 to 109.9 +/- 9.5 ml per minute per 1.73 m2 of body-surface area, P less than 0.01) and sodium excretion (17.0 +/- 5.9 to 31.7 +/- 7.2 mumol per minute, P less than 0.01) in patients with essential hypertension. The increase in glomerular filtration rate was most striking, averaging 33 per cent (66.0 +/- 10.3 to 88.0 +/- 9.2 ml per minute per 1.73 m2, P less than 0.001) in patients in whom an initial reduction was evident and hypertension was more severe. These observations suggest that a functional element, perhaps involving angiotensin-mediated renal vasoconstriction, frequently has a role in the reduction in glomerular filtration rate that occurs in essential hypertension. This class of agent may improve renal excretory function as it controls hypertension.

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.

Partial peripheral resistance to thyroid hormone

A 33 year old partially thyroidectomized woman was euthyroid when ingesting 500 microgram of L-triiodothyronine (T3) daily. Her condition was evaluated during therapy with daily T3 doses between 50 and 500 microgram. She was hypothyroid and had a markedly subnormal oxygen consumption rate when taking 50 to 100 microgram T3 daily, and oxygen consumption did not increase greatly above predicted normal values despite serum T3 concentrations up to 3,200 ng/dl. Her pulse rate, blood pressure, systolic time intervals and exercise tolerance changed minimally and remained within the normal range during the different dosage schedules. Urinary creatine and hydroxyproline, indices of muscle and skeletal protein catabolism, increased normally with higher T3 doses, but serum cholesterol, creatine phosphokinase, calcium and alkaline phosphatase did not change substantially. Basal and thyrotropin-releasing hormone (TRH) stimulated thyrotropin secretion were suppressed during all T3 doses. The prolactin response to TRH was normal at 50 microgram T3/day and was reduced by higher doses of T3. Absorption of T3, serum T3 protein binding and T3 metabolic clearance rates were all within normal limits. The findings in this patient are compared to clinical and biochemical findings in 17 previously described patients. The manifestations of peripheral thyroid hormone resistance are quite variable in the organ systems involved and in the degree of involvement. The molecular basis of the abnormality in our patient remains undefined.

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.