Gordon S. Stokes

Effects of Isosorbide Mononitrate and AII Inhibition on Pulse Wave Reflection in Hypertension

Abstract—The aortic pulse wave contour in isolated systolic hypertension often shows a prominent reflection peak, which combines with the incident wave arising from cardiac ejection so as to widen pulse pressure. We investigated the effects of an extended-release nitrate preparation and of 2 angiotensin II (AII) inhibitors (an AII receptor antagonist and an ACE inhibitor) on the aortic pulse wave contour and systemic blood pressure in hypertensive subjects with high augmentation index caused by exaggerated pulse wave reflection. Two double-blind, randomized, placebo-controlled crossover studies were carried out in a total of 16 elderly patients with systolic hypertension resistant to conventional antihypertensive therapy. In 1 study, pharmacodynamic responses to single doses of placebo, isosorbide mononitrate, eprosartan, and captopril were determined; in the other, single-dose isosorbide mononitrate and placebo were compared in subjects treated with AII inhibitors at baseline. Blood pressure was measured by sphygmomanometry and pulse wave components by applanation tonometry at the radial artery. All 3 agents were shown to decrease brachial systolic blood pressure, aortic systolic blood pressure, and aortic pulse pressure. Qualitative effects on the aortic pulse wave contour differed: augmentation index was not significantly altered by either captopril or eprosartan but was decreased (P <0.0001) by ≈50% of the placebo value with isosorbide mononitrate in both study groups. We propose that isosorbide mononitrate corrected the magnified wave reflection in systolic hypertension of these elderly patients by an effect that was distinct from that exercised by either acute or chronic AII inhibition.

Long-Term Effectiveness of Extended-Release Nitrate for the Treatment of Systolic Hypertension

Isosorbide mononitrate (ISMN) is effective in the short-term for decreasing systolic blood pressure, pulse pressure, and pulse wave reflection in patients with systolic hypertension. To determine whether tolerance negates the efficacy of this nitrate in the long-term, a placebo-controlled study was performed in which ISMN was withdrawn briefly in a group of patients (n=16) who had received extended-release ISMN 60 to 120 mg once daily for 16 to 109 months. Blood pressure and wave reflection were determined by 24-hour ambulatory recorder and tonometer, respectively. During a 4-hour delay of the regular morning dose of ISMN, mean systolic blood pressure was higher than with the regular ISMN dosing schedule (P<0.0001). The maximum placebo-active difference was 16±4 mm Hg. The corresponding difference in augmentation index (a measure of pulse wave reflection) corrected for heart rate was 25±4% (P<0.001). The difference in pulse pressure was 13±3 mm Hg (P<0.001). There was no significant difference in diastolic blood pressure. For a subgroup (n=12) in which the effects of a single ISMN dose had been determined at the initiation of regular ISMN therapy, the mean change in augmentation index was of similar magnitude to that observed in their initial study. Thus, tolerance does not seriously diminish the antihypertensive efficacy of ISMN used as adjunct therapy in the chronic treatment of systolic hypertension. This agent lowers systolic blood pressure sufficiently to achieve therapeutic goal in some patients refractory to conventional treatment regimens.

Systolic hypertension in the elderly: Pushing the frontiers of therapy: A suggested new approach

In elderly patients with systolic hypertension resistant to treatment with conventional therapy, increased aortic pulse wave reflection and a high augmentation index are often present. These findings are indicative of endothelial dysfunction and deficient generation of nitric oxide, a potent vasodilator in the arterial tree. In such patients, treatment with the nitric oxide donor extended‐release isosorbide mononitrate characteristically produces prompt and sustained falls in both pulse wave reflection and systolic blood pressure. The adjunct use of this nitrate produces useful additional decreases in systolic blood pressure ranging from 10 to 45 mm Hg, often achieving target blood pressure goals in isolated systolic hypertension. By combining this endothelium‐independent nitric oxide donor with angiotensin‐converting enzyme inhibitors or angiotensin II receptor blockers, the potential exists to address both the nitric oxide deficiency and endothelial dysfunction of the vascular endothelium in these patients. Other possibilities for synergism with this combination include complementary hemodynamic, circadian, and metabolic actions together with prevention of nitrate tolerance. Isosorbide mononitrate may also be used successfully with calcium channel blockers, β blockers, and diuretics.

Changing pattern of adrenalectomy at a tertiary referral centre 1970−2000

Background:  In 1987, a report from this unit described the changing indications for open adrenalectomy over a 15‐year period. The indications for adrenalectomy had switched from it being the principal therapeutic procedure used in advanced breast cancer in the early 1970s, to being predominately performed for Cushings disease or incidental, asymptomatic, adrenal masses by the early 1980s. The aim of the present study was to evaluate the changes in the presentation and management of adrenal disease in the last 15 years and to compare these findings with our previously published results.

The Relationship of Prorenin Values to Microvascular Complications in Patients with Insulin-Dependent Diabetes Mellitus

We have performed a cross-sectional analysis of the relationship between prorenin values and the microvascular complications of diabetes in a well controlled population of insulin-dependent diabetes mellitus (IDDM) subjects. One hundred and thirty-nine subjects (75 men, 64 women, age 44 +/- 17 years; duration of diabetes 19 +/- 15 years), formed the study group. Sixty-seven subjects (48.2%) had no complications, 55 (39.6%) had retinopathy alone, and 17 (12.2%) had retinopathy and albuminuria. Patients with no complications had lower prorenin values than those with microvascular complications (p < 0.001), whilst patients with both albuminuria and retinopathy had higher values than those with retinopathy alone (p < 0.05). Retinopathy was associated with duration of diabetes (p < 0.0001), diastolic blood pressure (p < 0.02) and albuminuria (p < 0.0001) while albuminuria was associated with prorenin (p < 0.02), serum triglyceride (p < 0.01) and retinopathy (p < 0.001). Patients with albuminuria were 5.5 times more likely to have raised prorenin values (>80 ng/mL/h) than those with normal albumin excretion [95% confidence interval (CI): 1.48-20.12] and those with retinopathy alone were 2.5 times as likely (95% CI: 1.19-5.15). Eighty patients with IDDM (40 males, 40 females; age: 47 +/- 17 years; duration of diabetes: 20 +/- 15 years), had retinal photography performed to determine the association between the severity of retinopathy and prorenin values. Retinopathy was more severe in patients with retinopathy and albuminuria than in those with retinopathy alone (p < 0.002). When the prorenin values of patients with more marked retinopathy (eye grade greater than 3) were compared, prorenin values of those with retinopathy and albuminuria were greater than those of patients with retinopathy alone [269 (139-1406) versus 91 (41-273) ng/mL/h: geometric mean (range); p < 0.05]. Furthermore, when patients without albuminuria were considered, there was no significant difference between the prorenin levels of patients with more severe retinopathy (eye grade >3) when compared to patients with lesser degrees of retinopathy [91 (41-273) versus 69 (23-375). In patients with microvascular complications, prorenin values were independently predicted by albuminuria (p < 0.0001) and diastolic blood pressure (p < 0.02) but not the severity of retinopathy. In conclusion, prorenin values are significantly associated with the presence of microvascular complications in patients with IDDM. The association with albuminuria may be stronger than the association with retinopathy.

STUDIES ON THE VASODILATOR ACTIONS OF BUCINDOLOL IN THE RAT

1. Experiments were performed in anaesthetized rats to investigate the vasodilator actions of the β‐adrenoceptor antagonist bucindolol. Bucindolol (3 mg/kg) lowered blood pressure significantly in rats pretreated with (i) prazosin (0.4 mg/kg) (ii) prazosin (0.4 mg/kg) plus propranolol (0.5 mg/kg) or (iii) labetalol (0.5 mg/kg). Thus, a portion of the hypotensive effect of bucindolol was independent of effects on α‐ or β‐adrenoceptors. This was attributed to direct vasodilatation.

Concurrence of Primary Aldosteronism and Renal-Artery Stenosis

1. An unusual clinical case is described in which renal artery stenosis (RAS) was found to coexist with adrenocortical hyperplasia, resulting in hypertension.

Erythrocyte Cation Transport is Sex-Related and is Modified by Oral Contraceptives

Cation transport across the erythrocyte membrane was studied in normotensive male and female subjects, 20 to 45 years of age. Inward sodium-potassium cotransport was found to be significantly greater in men than in women who were not taking oral contraceptives. Intracellular potassium concentration was lower in men than in women, and was inversely correlated with cotransport. Women who were using oestrogen-progestogen oral contraceptives had higher cotransport than those who were not. It is concluded that a difference in cotransport exists between Caucasian men and women, which is not evident if women are taking oral contraceptives, and which could invalidate comparisons of cation transport between subject groups that are not sex-matched.

Interactions of L-arginine, isosorbide mononitrate, and angiotensin II inhibitors on arterial pulse wave

BACKGROUND Deficiency of nitric oxide (NO) production has been implicated in the pathogenesis of increased pulse wave reflection associated with systolic hypertension. We investigated the effects on systolic blood pressure (BP) and pulse wave contour of two nitrate donors, isosorbide mononitrate (ISMN) and L-arginine. METHODS The subjects were 14 elderly patients chronically treated with antihypertensive agents. In seven of the subjects, agents causing angiotensin II (AII) inhibition (angiotensin-converting enzyme [ACE] inhibitor or AT(1) receptor antagonist, or both) were used. Study entry required systolic BP of 150 to 200 mm Hg, and aortic pulse wave augmentation more than 15 mm Hg. Pharmacodynamic responses to ISMN, L-arginine, and ISMN plus L-arginine, were assessed in double-blind crossover studies by standard sphygmomanometry and applanation tonometry. RESULTS Peripheral systolic BP, aortic systolic BP, and the aortic augmentation index were decreased (P <.001) by ISMN, irrespective of AII inhibition. L-arginine enhanced these effects (P <.001) in the subjects without AII inhibition, but not in those receiving AII inhibitors. Given without ISMN or AII inhibitors, L-arginine decreased peripheral systolic BP, but to a lesser extent than ISMN. CONCLUSIONS L-arginine has potential value as an adjunct to ISMN in combination with antihypertensive therapy in elderly patients with systolic hypertension. However, when given with single-dose ISMN, its vasodilator activity may overlap with that of AII inhibitors. Future studies of L-arginine in conjunction with chronic continuous ISMN dosing are warranted.

GENOTYPIC INFLUENCE ON PLASMA DIPEPTIDYL CARBOXYPEPTIDASE-1 ACTIVITY IN HYPERTENSIVES

1. Plasma dipeptidyl carboxypeptidase‐1 (DCP1; angiotensin I‐converting enzyme, kininase II; EC 3.4.15.1) tracks with the deletion allele in genotypes of a 287 bp insertion/deletion (I/D) polymorphism of its gene, DCP1, in healthy Caucasian populations. The aim of the present study was to see whether genotype has a similar influence on plasma DCP1 in hypertensives.