Manuel Morgado

Cyclic nucleotide-dependent relaxation pathways in vascular smooth muscle.

Vascular smooth muscle tone is controlled by a balance between the cellular signaling pathways that mediate the generation of force (vasoconstriction) and release of force (vasodilation). The initiation of force is associated with increases in intracellular calcium concentrations, activation of myosin light-chain kinase, increases in the phosphorylation of the regulatory myosin light chains, and actin-myosin crossbridge cycling. There are, however, several signaling pathways modulating Ca2+ mobilization and Ca2+ sensitivity of the contractile machinery that secondarily regulate the contractile response of vascular smooth muscle to receptor agonists. Among these regulatory mechanisms involved in the physiological regulation of vascular tone are the cyclic nucleotides (cAMP and cGMP), which are considered the main messengers that mediate vasodilation under physiological conditions. At least four distinct mechanisms are currently thought to be involved in the vasodilator effect of cyclic nucleotides and their dependent protein kinases: (1) the decrease in cytosolic calcium concentration ([Ca2+]c), (2) the hyperpolarization of the smooth muscle cell membrane potential, (3) the reduction in the sensitivity of the contractile machinery by decreasing the [Ca2+]c sensitivity of myosin light-chain phosphorylation, and (4) the reduction in the sensitivity of the contractile machinery by uncoupling contraction from myosin light-chain phosphorylation. This review focuses on each of these mechanisms involved in cyclic nucleotide-dependent relaxation of vascular smooth muscle under physiological conditions.

Pharmacist interventions to enhance blood pressure control and adherence to antihypertensive therapy: Review and meta-analysis

PURPOSE Pharmacist interventions to enhance blood pressure (BP) control and adherence to antihypertensive therapy in adults with essential hypertension were reviewed. METHODS A literature search was conducted to identify relevant articles describing pharmacist interventions intended to improve adherence to antihypertensive medications. Studies were included if they described a pharmacist intervention to improve medication adherence and analyzed adherence to therapy and BP control as outcomes. A fixed-effects model was used to combine data from randomized controlled trials. RESULTS A total of 15 studies were identified, testing 16 different interventions and containing data on 3280 enrolled patients. Although 87.5% of the interventions resulted in significant improvements in treatment outcomes, only 43.8% of the interventions were associated with significant increases in medication adherence. All interventions that increased antihypertensive medication adherence also significantly reduced BP. Almost all the interventions that were effective in increasing adherence to medication were complex, including combinations of different strategies. Meta-analysis of 2619 patients in 8 studies found that pharmacist interventions significantly reduced systolic blood pressure (SBP) (p < 0.001) and diastolic blood pressure (DBP) (p = 0.002) and that the meta-analytic differences in SBP and DBP changes from baseline to endpoint in intervention and control groups were -4.9 ± 0.9 mm Hg (p < 0.001) and -2.6 ± 0.9 mm Hg (p < 0.001), respectively. CONCLUSION A literature review and meta-analysis showed that pharmacist interventions can significantly improve medication adherence, SBP, DBP, and BP control in patients with essential hypertension. Interventions were complex and multifaceted and included medication management in all analyzed studies.

Predictors of uncontrolled hypertension and antihypertensive medication nonadherence

Background: Although hypertension is, in most cases, a controllable major risk factor in the development of cardiovascular disease, studies have demonstrated that hypertension remains poorly controlled in Portugal. Our aim was to evaluate the covariates associated with poor blood pressure (BP) control in a Portuguese hypertensive population. Patients and Results: We conducted a cross-sectional survey in a hospital hypertension outpatient clinic, located in the Eastern Central Region of Portugal. Patients attending the clinic from July to September 2009 were asked to participate in a structured interview including medication adherence and knowledge about hypertension. Eligible participants were all adults aged 18 or over with an established diagnosis of arterial hypertension and had been on antihypertensive drug treatment for at least 6 months. Exclusion criteria were dementia, pregnancy, and breastfeeding. Detailed clinical information was prospectively obtained from medical records. A total of 197 patients meeting the inclusion criteria and consenting to participate completed the interview. Of these, only 33.0% had their BP controlled according to the JNC 7 guidelines. Logistic regression analysis revealed three independent predictors of poor BP control: living alone (OR = 5.3, P = 0.004), medication nonadherence (OR = 4.8, P < 0.001), and diabetes (OR = 4.4, P = 0.011). Predictors of medication nonadherence were: unawareness of target BP values (OR = 3.7, P < 0.001), a report of drug side effects (OR = 3.7, P = 0.002), lack of BP monitoring (OR = 2.5, P = 0.015) and unawareness of medication indications (OR = 2.4, P = 0.021), and of hypertension risks (OR = 2.1, P = 0.026). Conclusions: Poor medication adherence, lack of information about hypertension, and side effects should be considered as possible underlying causes of uncontrolled BP and must be addressed in any intervention aimed to improve BP control.

PDE4 and PDE5 regulate cyclic nucleotides relaxing effects in human umbilical arteries

Cyclic nucleotides (cAMP and cGMP) are the main second messengers linked to vasodilatation. They are synthesized by cyclases and degraded by different types of phosphodiesterases (PDE). The effect of PDE inhibition and cyclases stimulation on 5-hydroxytryptamine (5-HT; 1 microM) and histamine (10 microM) contracted arteries was analysed. Stimulation of guanylate cyclase or adenylate cyclase relaxed the histamine- and 5-HT-induced contractions indicating that intracellular increase of cyclic nucleotides leads to vasodilatation of the human umbilical artery. We investigated the role of different PDE families in the regulation of this effect. The presence of the different PDE types in human umbilical artery smooth muscle was analysed by RT-PCR and the expression of PDE1B, PDE3A, PDE3B, PDE4C, PDE4D and PDE5A was detected. The unspecific PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX; 50 microM) relaxed histamine-contracted human umbilical artery on 47.4+/-7.2%. This effect seems to be due to PDE4 and PDE5 inhibition because among the selective PDE inhibitors used only the PDE4 inhibitor (rolipram; 1 microM) and the PDE5 inhibitors (dipyridamole and T0156; 3 microM and 1 microM respectively) induced significant relaxation (39.0+/-8.7, 30.4+/-6.0 and 36.3+/-2.8 respectively). IBMX, dipyridamole and T0156 produced similar relaxation on 5-HT-induced contraction. After forskolin, the addition of IBMX or rolipram increased the effect of the adenylate cyclase stimulator and almost completely relaxed the human umbilical artery contracted by histamine (92.5+/-4.9 and 90.9+/-4.7 respectively), suggesting a main role of PDE4. The data obtained with 5-HT contracted arteries confirmed this, because only rolipram and IBMX significantly increased the forskolin vasodilator effect. The administration of dipyridamole and T0156 after sodium nitroprusside (SNP) induced a significant increase of the SNP relaxant effect on histamine-contracted arteries, but PDE1 and PDE3 inhibition did not increase the effect of the guanylate cyclase stimulator. Similar effects were obtained in 5-HT contracted arteries, the SNP induced relaxation was increased by the PDE5 inhibition, but not by PDE1 or PDE3 inhibition. In summary, our results demonstrate that: 1) the increase of cAMP and/or cGMP levels induces relaxation of the human umbilical vascular smooth muscle; 2) four families of PDE are expressed in this smooth muscle: PDE1, PDE3, PDE4 and PDE5; 3) between these families, PDE4 and PDE5 are the key enzymes involved in the regulation of the relaxation associated to cAMP and cGMP, respectively.

Testosterone and cholesterol vasodilation of rat aorta involves L-type calcium channel inhibition.

Testosterone has rapid nongenomic vasodilator effects which could be involved in protective cardiovascular actions. Several authors suggested specific mechanisms to explain this effect, but this matter was not clarified yet. We studied the actions of testosterone and cholesterol on endothelium-denuded rat aorta and their effects on the L-type Ca2+ current (ICa,L) and potassium current (IK). Testosterone (1–100 μM) totally relaxed, in a rapid and concentration-dependent way, the aortic rings contracted by KCl or by (−)-Bay K8644 (BAY). Cholesterol also fully relaxed the contractions induced by KCl. None of the potassium channel antagonists tested (glibenclamide, tetraethylammonium and 4-aminopyridine) modified significantly the relaxant effect of testosterone. The antagonist of classic testosterone receptors, flutamide, did not modify the vasorelaxant effect of testosterone. Furthermore, testosterone and cholesterol inhibited either basal and BAY-stimulated ICa,L in A7r5 cells and they have no effects on IK. In summary, our results demonstrate that cholesterol and testosterone relax rat aorta by inhibiting LTCC. This effect of testosterone is not mediated by the classic hormone receptor or by potassium channel activation. These results suggest that the vasodilator mechanism of cholesterol and testosterone is the same.

Efficacy of Aliskiren/Hydrochlorothiazide Combination for the Treatment of Hypertension: A Meta-Analytical Approach

Background: Single-pill combinations of aliskiren/hydrochlorothiazide have recently been approved by the European Medicines Agency for the treatment of hypertension. Objective: This study aimed to assess the antihypertensive efficacy of aliskiren/hydrochlorothiazide combination in reducing systolic and diastolic blood pressure in hypertensive patients. Methods: A search in International Pharmaceutical Abstracts, MEDLINE, The Cochrane Library and ISI Web of Knowledge was performed from 2000 to November 2009, to identify randomized, double-blind, clinical trials using aliskiren/hydrochlorothiazide for the treatment of hypertension. Studies were included if they evaluated the antihypertensive efficacy of aliskiren/hydrochlorothiazide in patients with mild or moderate essential hypertension and age ≥ 18 years. The meta-analytical approach calculated the weighted average reductions of systolic and diastolic blood pressure for each daily dosage combination. Results: We included 5 clinical trials testing several combinations of aliskiren/hydrochlorothiazide and containing data on 5448 patients. In all studies blood pressure was assessed at inclusion (baseline) and after 8 weeks of therapy. Blood pressure reductions and control rates were significantly (p < 0.05) higher with the aliskiren/hydrochlorothiazide combinations than with placebo and the same doses of aliskiren or hydrochlorothiazide alone. The weighted mean reductions (mm Hg) from baseline of systolic and diastolic blood pressure for each aliskiren/hydrochlorothiazide combination were: -15.8/-10.3 (150/25 mg); -15.9/-11.8 (300/12.5 mg); -16.9/-11.6 (300/25 mg). Blood pressure control rates (%) for the above combinations were, at least, respectively: 43.8, 50.1 and 51.9. Conclusions: Aliskiren/hydrochlorothiazide provided clinically significant additional blood pressure reductions and improved blood pressure control rates over aliskiren or hydrochlorothiazide monotherapy.

Association of statin therapy with blood pressure control in hypertensive hypercholesterolemic outpatients in clinical practice

Background: Some clinical evidence revealed that statins, apart from lowering cholesterol levels, also have an antihypertensive effect. Our aim was to evaluate the existence of a possible association of statin therapy with blood pressure (BP) control in clinical practice. Materials and Methods: Patients attending a hypertension/dyslipidemia clinic were prospectively evaluated. Those patients with a diagnosis of stage 1 hypertension and hypercholesterolemia who consented to participate were included in the study, either in the statin group (when taking a statin) or in the control group (when not taking a statin). Exclusion criteria included dementia, pregnancy, or breastfeeding, and history or evidence of stage 2 hypertension. Detailed clinical information was prospectively obtained from medical records. A total of 110 hypertensive patients were assigned to the study (82 in the statin group and 28 in the control group). Results: Although there were no significant differences (P > 0.05) in both groups concerning gender, body mass index, antihypertensive pharmacotherapy, and serum levels of high-density lipoprotein cholesterol and triglycerides, a higher BP control was observed in the statin group (P = 0.002). Significantly lower systolic BP (–6.7 mmHg, P = 0.020) and diastolic BP (–6.4 mmHg, P = 0.002) levels were reported in the statin group. Serum levels of low-density lipoprotein were also significantly lower in the statin group (P < 0.001). Conclusions: This observational study detected an association of statin therapy with BP control in hypertensive hypercholesterolemic patients in clinical practice. These findings raise the possibility that statin therapy may be useful for BP control in the studied population.

Blood pressure control and antihypertensive pharmacotherapy patterns in a hypertensive population of Eastern Central Region of Portugal

BackgroundInterventions to improve blood pressure control in hypertension have had limited success in clinical practice despite evidence of cardiovascular disease prevention in randomised controlled trials.The objectives of this study were to evaluate blood pressure control and antihypertensive pharmacotherapy patterns in a population of Eastern Central Region of Portugal, attending a hospital outpatient clinic (ambulatory setting) for routine follow-up.MethodsMedical data of all patients that attended at least two medical appointments of hypertension/dyslipidemia in a university hospital over a one and a half year period (from January 2008 to June 2009) were retrospectively analysed. Demographic variables, clinical data and blood pressure values of hypertensive patients included in the study, as well as prescribing metrics were examined on a descriptive basis and expressed as the mean ± SD, frequency and percentages. Students test and Mann-Whitney rank sum test were used to compare continuous variables and χ2 test and Fisher exact probability test were used to test for differences between categorical variables.ResultsIn all, 37% of hypertensive patients (n = 76) had their blood pressure controlled according to international guidelines. About 45.5% of patients with a target blood pressure <140/90 mmHg (n = 156) were controlled, whereas in patients with diabetes or chronic kidney disease (n = 49) the corresponding figure was only 10.2% (P < 0.001). Among patients initiating hypertension/dyslipidemia consultation within the study period 32.1% had stage 2 hypertension in the first appointment, but this figure decreased to 3.6% in the last consultation (P = 0.012). Thiazide-type diuretics were the most prescribed antihypertensive drugs (67%) followed by angiotensin receptor blockers (60%) and beta-blockers (43%). About 95.9% patients with comorbid diabetes were treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.ConclusionsClinically important blood pressure decreases can be achieved soon after hypertension medical appointment initiation. However, many hypertensive patients prescribed with antihypertensive therapy fail to achieve blood pressure control in clinical practice, this control being worse among patients with diabetes or chronic kidney disease. As pharmacotherapy patterns seem to coincide with international guidelines, further research is needed to identify the causes of poor blood pressure control.

Factors influencing medication adherence and hypertension management revisited: recent insights from cancer survivors

Factors influencing medication adherence and hypertension management revisited: recent insights from cancer survivors