Current Hypertension Reviews - Volume 4, Issue 3, 2008

Pulmonary hypertension is not uncommonly seen in the critically ill. It may be encountered in patients with pre-existing diseases or may occur acutely without predisposing conditions. The diagnosis and management of pulmonary hypertension can be very challenging, given that critically ill patients are often concurrently haemodynamically unstable. Commonly used therapies in the Intensive Care Unit, such as fluid resuscitation, mechanical ventilation, vasopressors and inotropes may have deleterious effects in this population. We review the pathophysiology, diagnosis and current management strategies of this disease, with special emphasis on the critically ill adult population.

With-No-Lysine [K] (WNK) kinases are a group of serine/threonine protein kinases with an unusual location of the catalytic lysine. There are four mammalian WNK kinases, WNK1-4, each encoded by a separate gene. In addition, WNK1 has two alternatively spliced isoforms: a ubiquitously expressed full-length long isoform (L-WNK1) with kinase activity and a kidney-specific isoform (KS-WNK1) lacking kinase activity. Mutations of WNK1 and WNK4 genes cause a genetic hypertension syndrome, pseudohypoaldosteronism type 2 (PHA2). Recent studies show that WNK1, 3 and 4 are expressed in the aldosterone-sensitive distal tubules of kidney and contribute to sodium (Na+) and potassium (K+) homeostasis by regulating tubular Na+ and K+ transporters in complex manners. Mice with heterozygous disruption of WNK1 gene have hypotension but without apparent renal Na+ wasting. L-WNK1 is also expressed in heart and blood vessel. Thus, function of WNK1 in cardiovascular system may also contribute to blood pressure regulation. Transgenic or knockin mice carrying a disease-causing WNK4 gene exhibit typical phenotypes of PHA2 by increasing renal Na+ reabsorption. The review summarizes recent studies on the mechanism of WNK kinases regulation of Na+ homeostasis and cardiovascular function and the role in blood pressure control.

Approximately 65 million individuals in the United States suffer from systemic hypertension. Hypertension leads to various cardiovascular diseases including myocardial infarction, stroke, kidney disease, and others. Hypertension is commonly linked to other risk factors for cardiovascular diseases such as diabetes, dyslipidemia, and smoking. For this study, we reviewed 24 recently published papers that compared different hypertension drugs with other drugs or placebo in their effectiveness to reduce blood pressure and major primary end points. We hypothesized that some drugs reduce the primary end point above and beyond simply reducing the blood pressure. We categorized papers into a number of groups to determine how many papers showed that drug vs. placebo or one drug regimen versus another drug regimen could better reduce a primary clinical end point independent of a better reduction in blood pressure. We found four papers that showed a benefit of a pharmacological regimen on major clinical end points above and beyond reduction of blood pressure. These findings primarily involve drugs that affect the renin-angiotensin-aldosterone system.

The current pharmacological arsenal for treating hypertension includes diuretics, inhibition of the Renin- Angiotensin-Aldosterone (RAA) cascade and alpha blockade, often with inadequate results. Gap junction proteins, connexins (Cx), are ubiquitously expressed in organs involved in the pathogenesis of hypertension, namely brain, heart, vascular bed and kidney. Central to hypertension is increased vasomotor tone, itself determined by both paracrine mediators as well as by cell-cell interaction mediated by connexins. Four connexins are involved (Cx37, Cx40, Cx43 and Cx45); their expression patterns and function differ both in physiological conditions as well as in disease states such as hypertension and atherosclerosis. Cx37, Cx40 and Cx43 are expressed in endothelial cells, whereas Cx43 and Cx45 are mostly expressed in vascular smooth muscle cells. Animal models demonstrate a distinct role of Cx40 and Cx43 in renal hypertension. Furthermore, Cx40-deficient mice are constitutively hypertensive and a polymorphism in the promoter region of the encoding gene is associated with an increased risk of hypertension in humans; both observations imply an independent pathophysiological mechanism for the development of hypertension. Whether modifications of function and expression of connexins are markers or causative for disease remains to be determined. However, modulation of connexin-mediated communication may represent a novel therapeutic approach for hypertension.

By the analysis of our previous studies, functional and biochemical markers related to ETS exposure are discussed. 18 healthy never smokers, 12 men (67%), 6 women (33%), 21 to 55 years old (mean:34+/-9 ys.) underwent twice - in a smoking free environment and in the same environment polluted by 35 ppm carbon monoxide from cigarette smoking- brachial artery ultrasonography, exercise stress testing, heart rate (HR) and blood pressure (BP) monitoring, carboxyhemoglobin (COHb) dosage. In ETS exposure compared with no exposure, flow-mediated dilation mean value (FMD), assessed by ultrasonography, was 6.8+/-7.8% versus 12.6+/- 7.8%, significantly impaired; mean HR was 89+-4 beats/minute-for 2h duration- versus 77+/-4 beats/minute; systolic BP was 134+/-17 mmHg versus 124+/-21 mmHg; diastolic BP was 79+/-4 mmHg vs 76+/-5 mmHg, with no change. Bicycle exercise stress testing showed a significantly increase in mean time to recovery baseline parameters, 19.04+/-4 minutes versus 8.5 +/-4 minutes (P less than 0.01),and mean COHb was 1.7+/-0.4% vs 0.8+/- 0.4 (P less than 0.01). From the results observed, five markers of ETS exposure could be identified and, then, discussed:1. Impaired FMD, effect of endothelial dysfunction, 2. Transient increase in systolic BP; 3. HR increase; 4.Diminished tolerance to exercise; 5. Increased COHb blood concentrations.

It is well recognized that the proliferation of vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of various vascular diseases, including atherosclerosis and hypertension. It is generally considered that the phosphorylation/dephosphorylation reactions of a variety of enzymes belonging to the family of mitogen-activated protein kinases (MAPKs) play an important role in the transduction of mitogenic signal. We have previously shown that among extracellular signal-regulated protein kinases (ERKs), the 42 and 44 kDa isoforms (ERK1/2) participate in the cellular mitogenic machinery triggered by several VSMCs activators, including thrombin. ERK1/2 activation by G-protein-coupled receptors (GPCRs) has been shown to be Ca2+-dependent and to require the transactivation of epidermal growth factor receptor (EGFR). In addition, it is generally admitted that variations of the intracellular Ca2+ concentration ([Ca2+] i) play an important role in the transduction of mitogenic signal. Recently, we have shown that in thrombin-stimulated VSMCs, EGFR-independent activation of ERK1/2 activation could occur when agonist-induced ([Ca2+] i) elevation was reduced. This review examines recent findings in ERK1/2 signaling pathway that have been identified as critically important mediator of VSMCs hypertrophy and vascular diseases. Future investigations should now focus on the mechanisms of MAPK activation which might therefore represent a new mechanism involved in the antiproliferative effect revealed in this review.

There is an epidemic of the metabolic syndrome across the world, which is often associated with hypertension and other coronary risk factors. Insulin resistance is thought to play a key role in this condition. Several different mechanisms such as activation of renin-angiotensin system, enhancement of sympathetic nerve system, and hyperinsulinemia may underlie hypertension in metabolic syndrome. Unlike in other tissues, angiotensin II regulates renal proximal tubule transport in a biphasic manner. The molecular mechanism for the angiotensin II-mediated regulation of renal proximal transport has been recently clarified. On the other hand, insulin stimulates sodium transport in several nephron segments including proximal tubules. Recent data have shown that the sodium-retaining effect of insulin is paradoxically preserved in a mouse model of insulin resistance, which may be enhanced by sympathetic nerve activation. In this review, we will focus on the roles of abnormal renal proximal tubule sodium handling in hypertension.

Consistent with a straightforward, time-domain interpretation of Westerhof's classic circuit diagram of the 3- element Windkessel, we have concluded that measured aortic pressure is the instantaneous sum of a constant (P∞), a Windkessel/reservoir pressure, and a wave-related pressure. According to our interpretation, the resistive element interposed between the left ventricle and the resistance-capacitance (RC) filter is, in fact, a hydraulic resistance in the proximal aorta that defines the wave-related pressure. The RC filter subserves the Windkessel/reservoir function and is distributed anatomically within the large arteries. The lower potential (pressure) of the RC filter (P∞) is not zero or even venous or mean circulatory pressure, but rather a higher pressure (∼30-40 mmHg) toward which aortic pressure declines asymptotically during diastole. As previously recognized, the Windkessel/reservoir pressure describes aortic diastolic pressure very precisely; in the new paradigm, the addition of the wave-related pressure provides the complement that describes systolic pressure equally precisely. This new interpretation has several potential implications for our understanding of hypertension. Diastolic hypertension would seem to be related most directly to alterations in reservoir pressure, particularly P∞ and reservoir resistance. Systolic hypertension may be a function of several factors: wave reflection, increased proximal aortic resistance, and decreased aortic compliance.

To assess 24-hour BP levels in subjects with metabolic syndrome is essential, because hypertension, which is the most prevalent component in the syndrome, makes the major contribution to cardiovascular risk. Because BP levels in subjects with metabolic syndrome are prone to be elevated in an out-of-office setting (i.e., nocturnal hypertension, morning hypertension), measurement of home and/or ambulatory BP levels is a promising method for managing the syndrome. The best treatment approach for this complex condition is a multifactorial one, much emphasis has been placed on RAAS inhibition, which is one of the most important factors in the disease, although there has been no clear evidence that RAAS inhibitors are more effective than other drugs for treatment of metabolic syndrome. However, previous trials for treating hypertension have generally enrolled non-obese patients, and have enrolled more complicated high-risk patients, in whom the most important issue is BP lowering itself. here is thus a need to assess how to treat relatively younger subjects withmilder and/or high-normal hypertension, because the prevalence of such patients is expected to increase dramatically along with burgeoning obesity rates.