Manuel Velasco

DOPAMINE : PHARMACOLOGIC AND THERAPEUTIC ASPECTS

Dopamine is a biogenic amine synthesized in the hypothalamus, in the arcuate nucleus, the caudad, and various areas of the central and peripheral nervous system. It has been widely established that dopamine and its agonists play an important role in cardiovascular, renal, hormonal, and central nervous system regulation through stimulation of alpha and beta adrenergic and dopaminergic receptors. There are several agonists of dopamine-2 (DA 2 ) dopaminergic receptors, such as bromocriptine, pergolide, lisuride, quinpirole, and carmoxirole, which inhibit norepinephrine release and produce a decrease in arterial blood pressure; in some cases, bromocriptine and pergolide also reduce heart rate. From a therapeutic point of view, the above-mentioned agonists are used for treating Parkinsons disease, acting over DA 2 dopaminergic receptors of the nigrostriatal system. Bromocriptine and the other dopaminergic agonists mentioned act over DA 2 receptors of the tuberoinfundibular system, inhibiting prolactin release and decreasing hyperprolactinemia and tumor size. Among DA 1 receptor agonists, we can mention fenoldopam, piribedil, ibopamine, SKF 3893, and apomorphine (nonspecific). Activation of these receptors decreases peripheral resistance, inducing lowering of arterial blood pressure and increases in heart rate, sympathetic tone, and activity of the renin aldosterone system. Among DA 2 receptor antagonists, we can mention metoclopramide, domperidone, sulpiride, and haloperidol. From a therapeutic point of view, metoclopramide and domperidone are used in gastric motility disorders, and haloperidol is used in psychotic alterations. Antagonists of DA 1 receptors are SCH23390 and clozapine. Clozapine is used for treating schizophrenia.

Hypertension in seven Latin American cities: the Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study.

Background Little information is available regarding hypertension, treatment, and control in urban population of Latin America. Objective We aimed to compare blood pressure (BP) distribution, hypertension prevalence, treatment, and control in seven Latin American cities following standard methodology. Methods The Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study was a cross-sectional, epidemiologic study assessing cardiovascular risk factors using stratified multistage sampling of adult populations (aged 25–64 years) in seven cities: Barquisimeto (Venezuela; n = 1848); Bogotá (n = 1553); Buenos Aires (n = 1482); Lima (n = 1652); Mexico City (n = 1720); Quito (n = 1638); and Santiago (n = 1655). The prevalence of hypertension and high normal BP were determined based on 2007 European Society of Hypertension and European Society of Cardiology definitions. Results BP increased with age in men and women; pulse pressure increased mainly in the upper age group. The hypertension prevalence ranged from 9% in Quito to 29% in Buenos Aires. One-quarter to one-half of the hypertension cases were previously undiagnosed (24% in Mexico City to 47% in Lima); uncontrolled hypertension ranged from 12% (Lima) to 41% (Mexico City). High normal BP was also evident in a substantial number of each city participants (≈5–15%). Majority of population has other cardiovascular risk factors despite hypertension; only 9.19% of participants have no risk factors apart from hypertension. Conclusion From 13.4 to 44.2% of the populations of seven major Latin American cities were hypertensive or had high normal BP values. Most hypertensive patients have additional risk factors. Public health programs need to target prevention, detection, treatment, and control of total cardiovascular risk in Latin America.

Calcium antagonists and atherosclerosis protection in hypertension.

Calcium antagonists are effective in hypertensive patients of all ethnic groups, irrespective of age, dietary salt intake, salt-sensitivity status or plasma renin activity profile. Some prospective studies show that the calcium antagonists, nifedipine GITS and nitrendipine, reduce cardiovascular morbidity and mortality at least to the same extent as the diuretics. Other prospective studies are in progress to evaluate the effect of calcium antagonists on cardiovascular morbidity and mortality, and the progression of atherosclerosis in hypertensive patients. Calcium antagonists, especially the highly lipophilic amlodipine, lacidipine and nisoldipine, are shown to possess antioxidant properties. These drugs reduce the oxidation of LDL and its influx into the arterial wall, and reduce atherosclerotic lesions in animals. Platelet production of malondialdehyde, a marker of oxygen free radical formation, is suppressed by amlodipine, lacidipine or nifedipine in hypertensive patients. New evidence from long-term clinical trials of calcium antagonists indicates that these drugs can reduce the rate of progression of atherosclerosis in hypertensive and coronary heart disease patients. In the Regression Growth Evaluation Statin Study (REGRESS), co-administration of calcium antagonist, amlodipine or nifedipine with pravasatin caused a significant reduction in the appearance of new angiographic lesions. In the Verapamil in Hypertension and Atherosclerosis Study (VHAS), verapamil was more effective than chlorthalidone in promoting regression of thicker carotid lesions in parallel with a reduction in the incidence of cardiovascular events. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), amlodipine slowed the progression of early coronary atherosclerosis in patients with coronary artery disease. In a subprotocol of the Intervention as a Goal in the Hypertension Treatment (INSIGHT) study, nifedipine GITS significantly decreased intima-media thickness as compared to co-amilozide (hydrochlorothiazide + amiloride). Preliminary results of the European Lacidipine Study on Atherosclerosis (ELSA) show that lacidipine reduced the intima-media thickness progression rate as compared to atenolol. Thus, selective calcium antagonists are potential antiatherosclerotic agents.

Angiotensin II receptor antagonists role in arterial hypertension

Angiotensin II receptor blockers represent a class of effective and well tolerated orally active antihypertensive drugs. Activation of AT1 receptors leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone and promote growth of vascular and cardiac muscle. AT1 receptor blockers antagonise all those effects. Losartan was the first drug of this class marketed, shortly followed by valsartan, irbesartan, telmisartan, candesartan, eprosartan and others on current investigation. All these drugs have the common properties of blockading the AT1 receptor thereby relaxing vascular smooth muscle, increase salt excretion, decrease cellular hypertrophy and induce antihypertensive effect without modifying heart rate or cardiac output. Most of the AT1 receptor blockers in use controlled blood pressure during the 24 h with a once-daily dose, without evidence of producing tolerance to the antihypertensive effect and being with low incidence of side effects even at long term use. Monotherapy in mild-to-moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of thiazide diuretic is added, 60–70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme (ACE) inhibitors, diuretics, calcium antagonists and beta-blocking agents. AT1 receptor blockers are specially indicated in patients with hypertension who are being treated with ACE inhibitors and developed side effects such as, cough or angioedema. The final position in the antihypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted and seem promising.

The cold pressor test: pharmacological and therapeutic aspects.

In this review article we discuss several aspects of the physiology, diagnosis, and pharmacology of the cold pressor test. The cold pressor test has been used for the diagnosis of cardiovascular reactivity in normotensive and hypertensive subjects. Some authors have stated that the cold pressor test will identify normotensive candidates at future risk of suffering from hypertensive disease. Interestingly, not all antihypertensive drugs block the exaggerated pressor response induced by cold stress. The most beneficial compounds belong to the α- and β-blocker groups. Furthermore, several neurohormones such as norepinephrine, endothelins, prostaglandins, and angiotensin II have been reported to be released during cold exposure. The neurophysiology of cold pressor test indicates that after stress a great sympathetic discharge is induced at the spinal cord and terminal endings of the sympathetic nervous system. The release of norepinephrine is the cause of arteriolar vasoconstriction and elevation of blood pressure.

The Role of Adiponectin in Endothelial Dysfunction and Hypertension

It has been two decades since the discovery of adiponectin, and today its role in insulin resistance, inflammation, and atherosclerosis are areas of major interest. Production of adiponectin is reduced in all inflammatory processes and states of insulin resistance such as obesity, type 2 diabetes mellitus, and coronary artery disease. Adiponectin regulates carbohydrate metabolism, and may also regulate vascular homeostasis by affecting important signaling pathways in endothelial cells and modulating inflammatory responses in the subendothelial space. Clinical studies have demonstrated a relationship between serum adiponectin concentrations and the activity of the renin-angiotensin-aldosterone system (RAAS), causing changes in blood pressure. Antihypertensive therapy with angiotensin II receptor blockers (ARBs) has been demonstrated to increase adiponectin levels in 3-6 months. Adiponectin has also been shown to play a role in cardiac injury in modulation of pro-survival reactions, cardiac energy metabolism, and inhibition of hypertrophic remodeling. The effects of adiponectin on the cardiovascular system are believed to be partially mediated by the activation of 5’ adenosine monophosphate-activated protein kinase (AMPK) and cyclooxygenase-2 (COX-2) pathways, reducing endothelial cell apoptosis, promoting nitric oxide production, decreasing tumor necrosis factor-alpha (TNF-α) activity, and preventing atherosclerotic proliferation and smooth muscle cell migration. Further evaluation of biologically active forms of adiponectin and its receptor should help to clarify how obesity affects the cardiovascular system.

The Maracaibo city metabolic syndrome prevalence study: design and scope.

The metabolic syndrome (MS) is a conglomerate of interrelated risk factors-including obesity, atherogenic dyslipidemia, arterial hypertension, and insulin resistance-which exponentially increase the risk of developing cardiovascular disease and type 2 diabetes mellitus. The purpose of this study was to determine the prevalence of MS according to the criteria published by the International Diabetes Federation, in individuals of both sexes over 18 years of age. This is a cross-sectional study based on MS prevalence in a representative sample from the Maracaibo district, Zulia State. The population of Maracaibo, according to the last census in 2001, was 1,219,927 habitants, with a 2007 population estimation of 1,428,043 habitants according to the National Institute of Statistics (NIS). Likewise, NIS projects that for the year 2009, 59.7% of the population of Venezuela will have individuals over 18 years of age. Using these data, the sample for Maracaibo District corresponds to 1986 individuals with or above 18 years of age. The data recollection was conducted by health professionals and medicine students, previously trained. The participants were subject to inquiry previous written consent and a medical examination, and qualitative variables such as smoking habit, socioeconomic status, physical activity, race, alcoholism, and nutritional habits, and quantitative ones like blood pressure, anthropometry, and blood works were determined. There is clear evidence that there is a lack of research and validated values to use as reference in our country and maybe in Latin America. Taking into account all that has been exposed here, this study will serve as a pilot for the numerous statistical determinations that will soon come afterward, providing first-hand accurate evidence on the behavior of the MS in the Latin American populace.

Diabetes and hypertension physiopathology and therapeutics.

Diabetes mellitus by itself, is a frequent and increasing public health problem. The prevalence in most Western countries varies between 2 to 5% and it is rapidly increasing in Asiatic countries due to changes in dietary habits during the last years. The association between diabetes mellitus and hypertension has been described in 60 to 65% of diabetics. In hypertension we find insulin resistance mainly in skeletal muscle involving the conversion of glucose to glycogen independently of blood flow. The degree of resistance is related to the severity of hypertension and varies between races. States of hyperinsulinaemia and insulin-resistance have been postulated as causes and/or consequences of hypertension. Regardless of the type of diabetes, hypertension is two to three times more common among diabetics compared with non-diabetics. In this paper we propose to review the essential physiopathological mechanisms involved in this association that causes high morbidity and mortality rates and increases disability among the population involved.

Ppar-γ Agonists and Their Role in Type 2 Diabetes Mellitus Management

Type 2 diabetes mellitus and obesity are the most frequent endocrine-metabolic diseases in the world and their pathogenic basis are characterized by insulin resistance and insulin secretion defects that can be demonstrated through several alterations in carbohydrates, lipids, and protein metabolism. The peroxisome proliferator-activated receptors have been identified as key regulators of glucose and lipid metabolism, because they act as transcription factors that stimulate protein synthesis in a wide variety of processes (energetic metabolism, proliferation, and cellular differentiation), of which have been identified 3 types (α, β/δ, γ). The thiazolidenediones are compounds that act as agonists of the peroxisome proliferator-activated receptor-γ increasing the tissues sensibility (muscle, adiposity tissue, and liver) to the insulin action; that is why they are used nowadays in treatment of type 2 diabetes mellitus. These drugs produce several of adverse effects, such as weight increased, edema, anemia, pulmonary edema, and congestive cardiac failure. Even their use have been related for some studies to an increased in the myocardium infarct risk; this correlation has not been a strong determinant to remove them from the market.

Role of angiotensin II AT1 receptor blockers in the treatment of arterial hypertension.

Hypertension is a very common condition and the most important risk factor for the occurrence of cardiovascular events. The hyperactivity of the renin-angiotensin-aldosterone system is considered a cardiovascular risk factor in subjects with essential hypertension. The intrinsic vascular abnormality in which the renin-angiotensin-aldosterone system is clearly the milieu for the development of the pathologic changes in blood vessel walls is one of the causes of the establishment of hypertension. Many drugs with different mechanisms of action have been used for the treatment of hypertension and its vascular complications. Nevertheless, the utilities of many drugs are limited by their adverse effects. Continuous research in the search for new pharmacological agents for the treatment of hypertension has led to the development of angiotensin II receptor type AT1 blockers. The most important functions mediated by AT1 receptors include: vasoconstriction, induction of the production and release of aldosterone, renal reabsorption of sodium, cardiac cellular growth, proliferation of vascular smooth muscle, increase of peripheral noradrenergic action and the central activity of the sympathetic nervous system, stimulation of vasopressin release, and inhibition of renin release from the kidney. The angiotensin II receptor type AT1 blockers inhibit the interaction of angiotensin II with its AT1 receptor. These agents lower blood pressure without producing cough as a side effect since, unlike the angiotensin-converting enzyme inhibitors they do not influence the levels of bradykinin or substance P. Hence, these drugs are suitable for the treatment of hypertensive patients who require therapy with a drug blocking the effect of angiotensin-converting enzyme but cannot use angiotensin-converting enzyme inhibitors due to cough as a side effect.