Endothelial function and common carotid artery wall thickening in patients with essential hypertension.

Intimal-medial thickening of the carotid wall is considered an early marker of atherosclerosis. Endothelial function is impaired in the presence of various cardiovascular risk factors that are implicated in the pathogenesis of atherosclerosis. To evaluate the relationship between vascular reactivity and carotid intimal-medial thickening, in 44 (mean+/-SD age, 45.7+/-8.8 years; range, 28 to 60 years; 31 men and 13 women) patients with essential hypertension who had never been treated and whose history of increased blood pressure was no longer than 12 months, we evaluated several parameters: intimal-medial thickening of the common carotid arteries (by B-mode ultrasound); forearm vascular response (by strain-gauge plethysmography) to intrabrachial infusion of acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 microg/100 mL forearm tissue per minute), an endothelium-dependent vasodilator, or sodium nitroprusside (1, 2, and 4 microg/100 mL forearm tissue per minute), an endothelium-independent vasodilator; calculated minimal forearm vascular resistances (the ratio between mean arterial pressure and maximal forearm vasodilation induced by 13 minutes of ischemia and 1 minute of exercise); and left ventricular mass index (on echocardiography profile). Carotid wall intimal-medial thickening showed a significant (P<0.001) inverse correlation with vasodilation to acetylcholine (r=-0.58) and age (r=-0.40), whereas no correlation was observed with the response to sodium nitroprusside or with minimal forearm vascular resistances, left ventricular mass index, systolic and diastolic blood pressures, and plasma cholesterol and glucose levels. Moreover, vasodilation to acetylcholine showed no correlation with minimal forearm vascular resistances or left ventricular mass index. Although comparison of different vascular "districts," such as the forearm microcirculation and carotid artery, does not allow for a conclusive interpretation, the present data indicate that in patients with essential hypertension, carotid wall thickening is associated with reduced endothelium-dependent vasodilation and suggest that endothelial dysfunction might be involved in early arterial structural alterations.

[The rationale for drug combinations in the therapy of arterial hypertension]. / Il razionale delle associazioni farmacologiche nella terapia dell'ipertensione arteriosa.

The therapeutic goal of antihypertensive drug combination is to improve the hypotensive effect with a possible reduction in incidence and severity of side effects. This goal can be reached by taking into account both pharmacokinetic and pharmacodynamic properties of single antihypertensive drugs. As far as pharmacokinetics is concerned, the rationale is to combine drugs which reach efficient concentrations with low interdose fluctuations and long duration of action. Drug combination with these pharmacokinetic properties allows efficient control of blood pressure with reduction in blood pressure variability and with a favourable trough to peak (T/P) ratio. Moreover these combinations can improve patient compliance to treatment through simplification of the dosing scheme, efficient blood pressure control throughout the dosage interval and reduction of incidence and severity of side effects. The pharmacodynamic rationale requires the combination of drugs with different mechanisms of action, whose biohumoral interactions must exert at least an additive antihypertensive effect and reduce the incidence and severity of side effects of one or of each antihypertensive drug. Finally, dosage should be chosen according to the therapeutic goal as follows: where the hypotensive effect is the primary target, drug doses near the plateau of the dose-response curve must be used, while lower, but effective doses should be used in order to improve tolerability.

Trough:peak ratio of the blood pressure response to angiotensin converting enzyme inhibitors.

SHORT- VERSUS LONG-ACTING ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS: Although ACE inhibitors are widely used in the treatment of hypertension, there are few data on trough:peak ratios and the data are contradictory. Part of the explanation for this lies in differences in pharmacological properties. Depending on the kinetics of elimination, the trough:peak ratio of short- and long-acting ACE inhibitors has to be evaluated according to a dose regimen of twice or once a day, respectively, and must take account of the dose used, since long-acting ACE inhibitors appear to have a dose-dependent trough:peak effect. Further explanations for the contradictory trough:peak ratios reported for ACE inhibitors include measurement methods (clinic blood pressure versus ambulatory monitoring) and study design. TROUGH:PEAK RATIO: Data from randomly allocated, placebo-controlled studies indicate that both the short-acting ACE inhibitors captopril and quinapril given twice a day and the long-acting ACE inhibitors enalapril, lisinopril, benazepril and cilazapril given once a day have an acceptable trough:peak ratio (> 50%). The evidence suggests that when chemically different ACE inhibitors with similar kinetics of elimination are administered at equipotent doses, similar trough:peak ratios are obtained.

Clinical pharmacology of long-acting calcium antagonists: what relevance for therapeutic effects?

The pharmacologic goals of long-acting calcium (Ca) antagonists are to obtain effective drug concentrations with low interdose fluctuations and therefore a more efficacious hypotensive effect throughout the interval of administration, with a reduction in blood pressure variability. The therapeutic relevance of these pharmacologic properties could be more efficient prevention of target-organ damage (TOD) and improvement of treatment compliance. Because TOD seems to be more closely related to 24-h mean blood pressure and blood pressure variability, effective control of blood pressure throughout the entire dosage interval, with a concomitant reduction in blood pressure variability, may reduce TOD. However this hypothesis awaits validation in prospective studies. Long-acting Ca antagonists can improve medication compliance through the following mechanisms: a more favorable dosage schedule by avoidance of more than two doses daily during combination therapy and by allowing choice of timing of dosing; efficacy in reducing blood pressure, which can be assessed by the patients themselves; and reduction in incidence and severity of side effects. Lacidipine, a long-acting dihydropyridine Ca antagonist, when given at the dose of 4 mg once daily has a favorable trough:peak efficacy and reduces blood pressure variability. Moreover, compared with a shorter-acting dihydropyridine drug, lacidipine caused a lower incidence of adverse effects linked to vasodilation.