A. Pirrelli

Distinct and Combined Vascular Effects of ACE Blockade and HMG-CoA Reductase Inhibition in Hypertensive Subjects

Hypercholesterolemia and hypertension are frequently associated with elevated sympathetic activity. Both are independent cardiovascular risk factors and both affect endothelium-mediated vasodilation. To identify the effects of cholesterol-lowering and antihypertensive treatments on vascular reactivity and vasodilative capacity, we studied 30 hypercholesterolemic hypertensive subjects. They received placebo for 4 weeks, either enalapril or simvastatin for 14 weeks, and, finally, both medications for an additional 14 weeks. Postischemic forearm blood flow (MFBF) and minimal vascular resistance (mFVR) were used as indices of vasodilative capacity and structural vascular damage, respectively. Total (resting-stress-recovery phases) cardiovascular (blood pressure [BP] and heart rate [HR]) and regional hemodynamic (FBF and FVR) reactivity to stressful stimuli were calculated as area-under-the-curve (auc) (valuextime). Compared with baseline levels, simvastatin reduced total (TOT-C) and LDL cholesterol (LDL-C) (1.27 mmol/L, P<0.001 and 1.33 mmol/L, P<0.001, respectively). Enalapril also reduced TOT-C and LDL-C (0.6 mmol/L, P<0.001 and 0.58 mmol/L, P<0.05, respectively). MFBF was increased substantially by both treatments (P<0.001). Enalapril had a greater effect (-1.7 arbitrary units (AU), P<0.001) than simvastatin (-0.6 AU, P<0.05) on mFVR. During stress, FBF increased more with enalapril (4.4 FBFxminutes, P<0.001) than with simvastatin (1.8 FBFxminutes, P<0.01). Conversely, FVR stress response was reduced more with enalapril (9.1 FVRxminutes, P<0.001) than with simvastatin (2.9 FVRxminutes, P<0.01). During combination treatment, a significant (0.001>P<0.05) additive effect on hypercholesterolemia, structural vascular damage, BP, and FVR was shown. The findings suggest that angiotensin-converting enzyme (ACE) inhibition induces a larger reduction than HMG-CoA reductase blockade in vascular reactivity and structural damage in hypercholesterolemic hypertensive subjects.

Functional characterization of endothelin receptors in hypertensive resistance vessels.

OBJECTIVE The physiological and pathophysiological functions of endothelin-1 in modulating the regional blood flow of normal and spontaneously hypertensive rats (SHR) were studied in the perfused mesenteric vascular bed, a useful model for investigating resistance vessels. DESIGN AND METHODS We used 12-week-old SHR and Wistar-Kyoto (WKY) rats. Endothelin A (ETA) receptor responsiveness was evaluated by endothelin-1 (0.2-2 mumol/l) concentration-response curves, and repeated in the presence of indomethacin and the ETA and endothelin B (ETB) receptor antagonists BQ-485 and BQ-788, respectively. ETB receptor responsiveness was tested by sarafotoxin S6c concentration-response curves, obtained in the noradrenaline-precontracted mesenteric vascular bed, and repeated after treatment with BQ-788 and after endothelial denudation. RESULTS In both groups, endothelin-1 induced concentration-dependent contraction; SHR exhibited a markedly increased maximal effect compared with WKY rats (P < 0.01). BQ-485 produced a shift to the right for endothelin-1 concentration-response curves in both groups, with a higher pA2 (negative common logarithm of the antagonist that produces an agonist dose ratio of 2) value in SHR than in WKY rats (P < 0.01). The increase in the maximal effect produced by endothelin-1 in SHR was prevented by indomethacin, which also induced a significant increase in the endothelin-1 concentration producing the half-maximal response (EC50) in SHR (P < 0.05). Sarafotoxin S6c produced an ETB-dependent endothelium-mediated relaxant effect in WKY rats, which was not observed in SHR. CONCLUSIONS The higher vasoconstriction induced by endothelin-1 in SHR may be related to a greater number of available ETA receptors, due to the presence of an ETA receptor subtype. This mechanism may be linked to the production of prostanoids that add to the direct endothelin-1-evoked vasoconstriction. These results, together with the lack of relaxation in response to sarafotoxin S6c in SHR, suggest that an imbalance in the endothelin-1 ability to induce both contraction and relaxation is present in SHR with sustained hypertension, manifesting as a greater contractile effect evoked in this strain.

Extracellular Matrix Gene Expression in the Left Ventricular Tissue of Spontaneously Hypertensive Rats

The aim of this study was to investigate the extracellular matrix gene expression in the hypertrophied left ventricular tissue of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, at early and mature ages. Interestingly, with age, a marked increase (+85% and +187% at 25 and 30 weeks of age, respectively, p < 0.01, vs 5 weeks) in matrix metalloproteinase-1 (MMP-1) mRNA levels in SHR and a progressive decrease (-50%, -70%, -78%, -70% at 10, 15, 25 and 30 weeks, respectively, p < 0.01, vs 5 weeks) in WKY were seen. Moreover, mRNA levels were significantly lower in SHR at 5 weeks. The analysis of mRNA expression for the tissue inhibitor of metalloproteinase-1 (TIMP-1) showed a significant increase in WKY (+44% and +44%, vs 15 and 25 weeks, respectively, p < 0.05), whereas there were no significant changes in SHR with development. At 30 weeks TIMP-1 mRNA levels were significantly reduced in SHR. Temporal trends of procollagen alpha1(I) and procollagen alpha1(III) mRNA levels were similar in both strains, but lower levels for procollagen alpha1(III) were found in SHR at 5 and 30 weeks. Although no significant differences were measured between the strains, mRNA levels for fibronectin were found decreased in WKY and increased in SHR with age. The results of the present study suggest an altered balance between collagen deposition and collagen degradation with development in this model of left ventricular hypertrophy and hypertension.

Mitochondrial energy metabolism in the left ventricular tissue of spontaneously hypertensive rats: abnormalities in both adeninenucleotide and phosphate translocators and enzyme adenylate-kinase and creatine-phosphokinase activities.

The aim of this study was to investigate the oxidative phosphorylation and additional adenosinetriphosphate (ATP) production mechanisms in mitochondria isolated from hypertrophied left ventricles of spontaneously hypertensive rats (SHR). Measurements of adenosinediphosphate (ADP)/ ATP and inorganic phosphate (Pi) carrier activities showed a significant reduction of Vmax values thus suggesting a general decrease of ATP supply in the hypertrophied ventricles. Investigation of mitochondrial enzyme activities showed 45% and 90% increases of adenylate-kinase and 80% and 110% increases of creatine-phosphokinase in 5- and 24-week-old SHR, before and after the development of the hypertensive state, respectively. The abnormalities found in SHR at the mitochondrial level suggest a profound rearrangement of energy production mechanisms in this model of left ventricular hypertrophy; whether the defects are determined genetically, and then worsen with the hypertensive state, remains to be determined.

Antihypertensive efficacy of manidipine and enalapril in hypertensive diabetic patients.

Recent studies showed that in diabetic hypertensive patients, administration of angiotensin-converting enzyme (ACE)-inhibitors or calcium antagonists can effectively lower blood pressure (BP) and prevent diabetes-related cardiovascular complications with no adverse metabolic effects. We sought to assess the antihypertensive and metabolic effects of the new dihydropyridine calcium antagonist manidipine (M) in patients with diabetes mellitus and essential hypertension as compared with the ACE inhibitor enalapril (E). After 3 weeks of placebo, 101 (62 men; age range, 34-72 years) hypertensives with type II diabetes mellitus were randomized to M 10-20 mg or E 10-20 mg, od, for 24 weeks. At the end of the placebo period and the active-treatment phase, BP was measured with a mercury sphygmomanometer (office, O) and over the 24 h by ambulatory (A) monitoring. ABP recordings were analyzed to obtain 24-h, day (6 a.m. to midnight), and night (midnight to 6 a.m.) average systolic (S) and diastolic (D) BP and heart rate (HR) values. Homogeneity of the antihypertensive effect over the 24 h was assessed by the smoothness index [SI: i.e., the ratio between the average of the 24 hourly BP changes after treatment and the corresponding standard deviation (the higher the SI, the more uniform is the BP control by treatment over the 24 h]. The O SBP and DBP were significantly (p < 0.01) and similarly reduced by M (16 +/- 10 and 13 +/- 6 mm Hg, n = 49) and E (15 +/- 10 and 13 +/- 6 mm Hg, n = 45). The percentage of patients whose O DBP was reduced < or = 85 mm Hg (i.e., the value indicated to be the optimal DBP goal in diabetic hypertensives) was similar for M (37%) and E (40%). The reduction of 24-h BP also was similar between M (n = 38) and E (n = 38) for both drugs (systolic, 6 +/- 11 and 8 +/- 10 mm Hg; diastolic, 5 +/- 8 and 5 +/- 7; NS, M vs. E). The antihypertensive effect was distributed in a similar homogeneous fashion throughout the dosing interval, as shown by the similar SI values (M, 0.6 +/- 1.2 for SBP and 0.6 +/- 0.9 for DBP; E, 0.6 +/- 0.8 for SBP and 0.5 +/- 0.7 for DBP; NS, M vs. E). O and A HR were unchanged by either treatment. Markers of glucose and lipid metabolism and renal function were not significantly modified by treatment both with M and with E. In the diabetic hypertensives, M was as effective and metabolically neutral as the ACE-inhibitor E.

Endothelin-1-receptor-mediated responses in resistance vessels of young and adult spontaneously hypertensive rats.

Objective To assess whether primary changes in endothelin-1 (ET-1) receptor responsiveness or secondary vessel functional modifications could characterize the effects evoked by ET-1 in the mesenteric vascular bed (MVB) of prehypertensive 5-week-old and 12-week-old spontaneously hypertensive rats (SHRs). Design and methods We used male 5-week-old and 12-week-old SHRs and sex- and age-matched Wistar-Kyoto (WKY) rats as controls. ET-1 receptor responsiveness was evaluated by ET-1 (0.04–2 μmol/l) concentration-response curves and repeated with indomethacin and BQ-123 (0.1–0.5 μmol/l), the latter a selective ETA receptor antagonist. ETB receptor responsiveness was tested by sarafotoxin S6c (1–100 nmol/l) and IRL-1620 (0.1–10 nmol/l) concentration-response curves, obtained in the noradrenaline-precontracted MVB. Results At 5 weeks of age, ET-1 induced a similar concentration-dependent contraction in SHRs and WKY rats, with an overlapping BQ-123 pA2 value (negative common logarithm of the antagonist that produces an agonist dose ratio of 2) in the two strains. Indomethacin was ineffective in both groups. Sarafotoxin S6c and IRL-1620 both evoked an ETB-mediated, significant relaxation, only in WKY rats. In 12-week-old SHRs, ET-1 evoked a markedly increased maximal effect compared with the response in WKY rats (P < 0.01); this was prevented by treatment with indomethacin. The BQ-123 pA2 value was higher in SHRs than in WKY rats (P < 0.01). Both sarafotoxin S6c and IRL-1620 evoked a significant concentration-dependent relaxation in WKY rats, which was not detected in SHR preparations. Conclusions Our results could suggest that the different responses evoked by ET-1 in the MVB of SHRs during the onset of hypertension may be related partially to primary alterations in the ET-1 receptorial pattern and partially to the onset of high blood pressure, leading to an impairment in the haemodynamic balance.

Stress-induced hemodynamic responses are associated with insulin resistance in mild hypertensives

BACKGROUND High blood pressure (BP) and pulse pressure (PP) are recognized as independent risk factors for cardiovascular diseases, whereas insulin resistance (IR) is often associated with hypertension. The purpose of the study was to verify whether PP, taken at the doctors office and during laboratory stimuli, might be predictive of IR. METHODS Homeostasis model assessment insulin resistance index (HOMA) was calculated in 75 grade 1 hypertensives (148 +/- 2/92 +/- 1 mm Hg). Then, patients underwent hemodynamic reactivity study, induced by color word stroop, cold pressor, and handgrip tests. Stress response was calculated as total area (value x time) - baseline area (baseline value x time). RESULTS Patients with similar age, history of hypertension, blood lipids and office blood pressure, but different HOMA (IR-low: 36.3 +/- 1.7 v IR-medium: 62.6 +/- 1.6, P <.001; IR-high: 123.1 +/- 12.8, P <.001 v IR-low and IR-medium), were divided in tertiles. They demonstrated a significant reactivity of systolic BP (IR-low: 225 +/- 58 v IR-medium: 448 +/- 43, P <.01; IR-high: 625 +/- 55, P <.001 v IR-low and P <.01 v IR-medium), PP (IR-low: -8 +/- 19 v IR-medium: 83 +/- 13, P <.001; IR-high: 201 +/- 19, P <.001 v IR-low and IR-medium), and stroke volume (SV) (IR-low: -138 +/- 43 v IR-medium: 1 +/- 27, P <.01; IR-high: 28 +/- 24, P <.001 v IR-low), but similar arterial stiffness (PP/SV) response. Partial correlation between IR and hemodynamic measurements showed a significant association only for systolic BP (0.54, P <.001), PP (0.686, P <.001), and SV (0.384, P <.001) reactivity, but not for office and baseline values. Stepwise multiple regression showed that only PP (beta: 0.634, P <.001) and, among hemodynamic determinants, SV (beta: 0.401, P <.001) response entered into the equation. CONCLUSIONS The findings demonstrate that increased stress-induced PP, maintained by SV response, is the most predictive hemodynamic variable of reduced insulin sensitivity in mild hypertensives.

Antihypertensive effects of six calcium antagonists: evidence from Fourier analysis of 24-hour ambulatory blood pressure recordings

Abstract Background: Blood pressure is characterized by a circadian rhythm, with lower values during sleep and periods of minimal activity, and higher values during the day and periods of mental and physical activity. An increased blood pressure variability has been reported to contribute independently to the higher cardiovascular risk of hypertensive patients; reducing this variability has therefore become an important goal of antihypertensive treatment. Objective: The aim of this study was to assess the ability of various calcium channel antagonists to reduce 24-hour average blood pressure and to study the effect of these agents on blood pressure variability, particularly on the blood pressure variations between day and night and the slope of the blood pressure increase that typically occurs in the morning at awakening. Methods: A total of 110 patients with grade 1 or grade 2 essential hypertension (diastolic blood pressure 90–109 mm Hg) were randomly assigned to receive nifedipine slow release (SR) 20 mg BID (n = 20), nifedipine gastrointestinal therapeutic system 60 mg QD (n = 20), amlodipine 10 mg QD (n = 20), felodipine extended release (ER) 10 mg QD (n = 15), verapamil SR 240 mg QD (n = 20), or lercanidipine 10 mg QD (n = 15) for 4 months. Each patients blood pressure was monitored in ambulatory conditions over 24 hours before treatment and after 2 and 4 months of treatment. The 24-hour, daytime, nighttime, and hourly average values and trough-to-peak ratios were computed. Original data series were also analyzed by means of a Fourier model with 4 harmonics, and the blood pressure increase per time unit in the morning was computed. Results: The study sample included 60 men and 50 women (mean age ± SD, 53.2 ± 1.9 years). Based on the Fourier analysis, all patients in each treatment group experienced improvement in their blood pressure profile. With the exception of felodipine ER, all the compounds studied induced a significant ( P P Conclusions: Given the link between blood pressure fluctuations and cardiovascular risk, all new antihypertensive drugs should be tested for their ability not only to reduce 24-hour mean blood pressure levels, but also to maintain physiologic 24-hour blood pressure profiles and to prevent excessive blood pressure fluctuations.

Carrier-mediated transport controls hydroxyproline catabolism in heart mitochondria from spontaneously hypertensive rat

In this study we have investigated hydroxyproline transport in rat heart mitochondria and, in particular, in heart left ventricle mitochondria isolated from both spontaneously hypertensive and Wistar‐Kyoto rats. Hydroxyproline uptake by mitochondria, where its catabolism takes place, occurs via a carrier‐mediated process as demonstrated by the occurrence of both saturation kinetics and the inhibition shown by phenylsuccinate and the thiol reagent mersalyl. In any case, hydroxyproline transport was found to limit the rate of mitochondrial hydroxyproline catabolism. A significant change in V max and K m values was found in mitochondria from hypertensive/hypertrophied rats in which the K m value decreases and the V max value increases with respect to normotensive rats, thus accounting for the increase of hydroxyproline metabolism due to its increased concentration in a hypertrophic/hypertensive state.

Multicenter, double-blind clinical trial with different doses of pinacidil in patients with mild-to-moderate essential hypertension☆

Abstract The antihypertensive efficacy and therapeutic safety of pinacidil, 12.5 or 25 mg twice daily (BID), were assessed in a multicenter, double-blind, crossover trial. Seventy-seven patients (mean age, 47.3 years) with mild-to-moderate essential hypertension were enrolled in the study and randomly assigned to one of the following schedules: sequence A: pinacidil 12.5 mg BID for 3 weeks; 1-week washout period (two placebo capsules per day); pinacidil 25 mg BID for 3 weeks. Sequence B: pinacidil 25 mg BID for 3 weeks; 1-week washout (two placebo capsules per day); pinacidil 12.5 mg BID for 3 weeks. Both drug doses (25 or 50 mg/d) were equally effective, producing a similar and significant reduction in systolic and diastolic blood pressures in the sitting and standing positions. Systolic blood pressure was reduced by approximately 7% to 8% from baseline in both sequences A and B. Diastolic blood pressure, measured in both positions, was reduced by 8% to 9% from baseline. Heart rate did not appear to be influenced by either dose. Analysis of variance showed no significant differences between the sequences; the only highly significant difference was between the times ( P