Effect of losartan on angiotensin II-mediated endothelin and prostanoid excretion in humans.

Angiotensin II (Ang II) stimulates renal prostanoid and vascular endothelin-1 (ET-1) release. Most known Ang II effects are mediated by AT1 receptors. Our aim was to determine whether AT1 receptor activation mediates Ang II-evoked renal prostanoid and ET-1 release. Eleven healthy men were randomized in a crossover, double-blind fashion to receive 100 mg/day of losartan or matching placebo, for 8 days. Blood and urine were sampled before and after a 2-h infusion of Ang II at a rate previously determined to increase mean arterial pressure (MAP) by 25 to 30 mm Hg in each subject. After a 14-day washout, subjects received the alternate treatment. Pretreatment with losartan had little effect on baseline MAP, but increased plasma renin activity, and virtually eliminated the pressor response to Ang II infusion. Angiotensin II significantly increased prostanoid excretion after placebo; the prostanoid response to Ang II was even greater after losartan. Plasma ET-1 was not altered by Ang II infusion, with or without losartan. In contrast, urine ET-1 excretion rate decreased to 40% of baseline after Ang II but not after losartan pretreatment; losartan alone had no effect. We conclude that Ang II decreases renal ET-1 synthesis and release through the AT1 receptor. In contrast, Angiotensin II-mediated renal prostanoid synthesis does not require activation of AT1 receptors. These findings indicate that AT1 receptor antagonists could provide renal protection through indirect mechanisms.

Fenofibrate lowers blood pressure in two genetic models of hypertension.

Fenofibrate, a commonly used lipid lowering drug, induces the expression of the gene coding for cytochrome P450-4A, whose major product is 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a potassium channel antagonist, could increase or decrease blood pressure (BP). We studied the effects of four weeks of oral fenofibrate on BP, urine output (UVol), plasma renin activity (PRA), and urine protein excretion in young (4-5 weeks) stroke prone spontaneously hypertensive rats (SHRSP), older (25 weeks) SHRSP, Dahl salt sensitive rats (Dahl S) on a high salt diet, Dahl S rats on a normal salt diet, and normotensive Sprague-Dawley (SD) rats. Fenofibrate prevented the increase in BP in 4-5 week old SHRSP, reduced BP in 25 week old SHRSP, but had no effect on BP in normotensive SD rats. Similarly, fenofibrate prevented the increase in BP in Dahl S rats on a high salt diet, but had no effect in Dahl S rats on a low salt diet. Fenofibrate increased UVol (and reduced weight gain) in young SHRSP and tended to increase it in other groups. It also increased PRA 2 to 5-fold in all groups except older SHRSP. Young SHRSP receiving fenofibrate excreted significantly less urine protein than control rats. The drug reduced proteinuria in Dahl S rats on high salt diet, but had no significant effect on proteinuria in other groups. In summary, fenofibrate reduced blood pressure and weight gain, increased UVol and PRA, and reduced urine protein excretion in young SHRSP. Other groups of animals showed these changes to a variable, but directionally similar extent. These findings are consistent with a natriuretic effect of fenofibrate.

A cardiovascular risk factor reduction clinic.

OBJECTIVE: To describe a cohort of patients referred to a cardiovascular risk factor reduction unit (CRFRU). DESIGN: Prospective cohort study. SETTING: Out-patients referred to a specialty clinic in a tertiary care hospital. PATIENTS: Seven hundred and four consecutive male and female patients with one or more cardiovascular risk factors, of whom 388 were reassessed after one year. INTERVENTIONS: Standard risk factors were measured in all participants. The probability of coronary artery disease (CAD) was assessed according to the Framingham equation and results were compared with data from the Saskatchewan Heart Health Survey for the general population of Saskatchewan. Patients received dietary and fitness advice, as well as drug therapy when indicated. For follow-up studies, the change in probability of CAD and selected variables after one year were measured. MAIN RESULTS: Patients referred to the CRFRU were at considerably higher risk for CAD than the general population. One hundred and sixty-eight of 235 men and 77 of 153 women seen in follow-up had a reduced risk score. Those who improved had a favourable change in systolic blood pressure and in their lipid profile, as well as greater weight loss. CONCLUSIONS: A CRFRU is feasible and appears to reduce risk in a considerable proportion of patients.

Effects of ridogrel, a thromboxane synthase inhibitor and receptor antagonist, on blood pressure in the spontaneously hypertensive rat.

Ridogrel is a dual acting thromboxane synthase inhibitor/TP receptor antagonist. We examined the effects of single and multiple doses on systolic blood pressure in stroke-prone spontaneously hypertensive rats. Single doses of ridogrel (5 to 125 mg/kg) did not affect systolic blood pressure or furosemide-stimulated excretion rates of thromboxane B2 or 6-keto-prostaglandin F1alpha, although ex vivo serum thromboxane B2 was dose-dependently reduced up to 95%. In contrast, repeated dosing (7 days) with ridogrel (3 to 25 mg/kg/day), had an antihypertensive effect in 12-week-old stroke-prone spontaneously hypertensive rats. At 25 mg/kg/day, ridogrel reduced systolic blood pressure from 200+/-6.1 to 173+/-6.7 mmHg (n=12, P<0.01). Ridogrel dose-dependently reduced serum thromboxane B2 and increased plasma renin activity. Unlike single doses, repeated dosing reduced urinary thromboxane B2 excretion (from 103+/-7 ng/day to 49+/-10 ng/day, P<0.01) while preserving 6-keto-prostaglandin F1alpha excretion. Ketoprofen, a cyclo-oxygenase inhibitor, (10 mg/kg/day for 7 days), depressed urine 6-keto-prostaglandin F1alpha in addition to attenuating serum and urine thromboxane B2. Ketoprofen prevented the antihypertensive effects of ridogrel. Ridogrel did not lower systolic blood pressure in Sprague-Dawley rats. We conclude that the antihypertensive effect of ridogrel involves preserving renal prostaglandin synthesis during thromboxane attenuation.

Pharmacoeconomics of hypertension control: basic principles of economic evaluation.

Pharmacoeconomics, the science of assigning costs and outcomes of drug therapy can be applied to antihypertensive drug therapy. There are five principle tools: cost identification, cost minimization, cost benefit, cost effectiveness and cost utility. If only drug aquisition costs are considered, there are marked differences among antihypertensive drug classes. These differences become less marked when the costs per quality adjusted life year are calculated. Often, differences among patients rather than differences among drug prices account for the bulk of variation.

Comparative pharmacology of calcium antagonists.

OBJECTIVE: To compare clinically relevant pharmacokinetic, pharmacodynamic and toxico logical characteristics of calcium-modulating compounds used in ischemic heart disease. DATA SOURCES: A MEDLINE search (1990 pt B to 1991 pt A revised for 1993; 1991 pt B to 1992 revised for 1993; and January to May 1993) combining the search phrases 'calcium channel blockers', 'myocardial ischemia', 'pharmacodynamics' and 'pharmacokinetics', and a search in Compact Cambridge Drug Information Source vol-6 (revised 1992, fourth quarter) using the search phrase 'calcium antagonists' and medical subject headings (MeSH) 'pharmacokinetics' and 'pharmacodynamics' were used to obtain title and abstract information on available current literature. STUDY SELECTION: Review articles, proceedings and studies published in English and available within the University of Saskatchewan library system, as they appeared to relate closely to the objective, were obtained for closer evaluation. In addition, primary references were examined, and journal reprints were selected from the authors' files. DATA EXTRACTION: The focus was on studies and objective reviews that profiled one or more representative compounds in a manner suitable for deriving background and comparative information pertaining to the objective. Data from multiple studies, or from studies that employed multiple methodological approaches, were preferentially extracted and summarized for presentation. DATA SYNTHESIS: The role of calcium in cardiac and vascular smooth muscle physiology was reviewed, highlighting the major mechanisms responsible for maintaining calcium homeostasis in these cells. With a focus on verapamil, diltiazem and 1,4-dihydropyridines currently employed in the treatment of cardiovascular disorders, a general survey of their sites of action, tissue selective pharmacodynamics, pharmacokinetic properties and side effects was undertaken in a comparative context. CONCLUSIONS: Calcium antagonists are employed in the treatment of angina, certain cardiac arrhythmias and hypertension. They are a chemically and pharmacologically heterogeneous group of compounds that act principally to inhibit the influx of calcium across certain voltage-dependent membrane channels. Concepts pertaining to calcium mobilization in the pathophysiology of myocardial ischemia, particularly at the molecular level, have evolved remarkably over the past decade. The repertoire of agents having calcium-regulating properties has expanded in parallel. The task of integrating new knowledge in both of these areas requires further attention in order to determine optimal approaches to treatment.

Drug therapy for hypertension: where we are, and where we might be heading.

The past two decades have witnessed major improvements in antihypertensive drug therapy. Although diuretics and beta-adrenergic antagonists remain the drugs of choice, we now recommend much lower doses than we previously did. This appears to achieve equal blood pressure control while causing fewer side effects. Angiotensin-converting enzyme inhibitors and calcium antagonists are newer, relatively expensive drug classes whose benefits can be exploited in certain subgroups of patients. Whether they will lead to improved outcome in the uncomplicated hypertensive patient remains uncertain. New classes of drugs affecting the renin-angiotensin system are in various stages of development. Again, they have theoretical advantages over those currently available. Still other classes--thromboxane synthase or receptor antagonists and endothelin antagonists--appear promising in animal studies. Finally, in future, it may be possible to cure hypertension by altering a patient's genetic make-up.