Severe Form Of Hypertension Research Articles

Type 2 Deiodinase Thr92Ala Polymorphism Is Not Associated With Arterial Hypertension in Type 2 Diabetes Mellitus Patients

To the Editor: A single nucleotide polymorphism in Type 2 deodinase ( Dio2 ) gene (A/G) in humans, in which a threonine (Thr) changes to alanine (Ala) at codon 92 (Thr92Ala), has been associated with a lower glucose disposal rate and higher insulin resistance in type 2 diabetes (DM2) patients.1,2 Nevertheless, these findings were not replicated in larger studies.3,4 Recently, Gumieniak et al reported that the Ala allele increases the risk for development of arterial hypertension.5 Since insulin resistance can cause hypertension, we sought to extend …

Impaired Protein Stability of 11β-Hydroxysteroid Dehydrogenase Type 2

Apparent mineralocorticoid excess (AME) is a severe form of hypertension that is caused by impaired activity of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which converts biologically active cortisol into inactive cortisone. Mutations in HSD11B2 result in cortisol-induced activation of mineralocorticoid receptors and cause hypertension with hypokalemia, metabolic alkalosis, and suppressed circulating renin and aldosterone concentrations. This study uncovered the first patient with AME who was described in the literature, identified the genetic defect in HSD11B2, and provided evidence for a novel mechanism of reduced 11beta-HSD2 activity. This study identified a cluster of amino acids (335 to 339) in the C-terminus of 11beta-HSD2 that are essential for protein stability. The cluster includes Tyr(338), which is mutated in the index patient, and Arg(335) and Arg(337), previously reported to be mutated in hypertensive patients. It was found that wild-type 11beta-HSD2 is a relatively stable enzyme with a half-life of 21 h, whereas that of Tyr(338)His and Arg(337)His was 3 and 4 h, respectively. Enzymatic activity of Tyr(338)His was partially retained at 26 degrees C or in the presence of the chemical chaperones glycerol and dexamethasone, indicating thermodynamic instability and misfolding. The results provide evidence that the degradation of both misfolded mutant Tyr(338)His and wild-type 11beta-HSD2 occurs through the proteasome pathway. Therefore, impaired 11beta-HSD2 protein stability rather than reduced gene expression or loss of catalytic activity seems to be responsible for the development of hypertension in some individuals with AME.

Accessory Renal Arteries—Mostly, But Not Always, Innocuous

Since the classical observation of Harry Goldblatt ([1][1]), hyperreninism resulting from renal ischemia has become an established paradigm to explain several forms of hypertension. The closest human counterparts to the experimental model of Goldblatt are the various forms of renal artery stenosis,

Baroreflexes in Hypertension

To date, most studies investigating baroreflexes in hypertension have been performed either by recording baroreflex afferents or by denervating them. In the current issue of Hypertension , Lohmeier et al1 present data on the effects of chronic carotid sinus stimulation (CSS) in hypertensive animals. Striking differences were observed during CSS in dogs with angiotensin II (Ang II)-induced hypertension as compared with control conditions. In line with a previous study,2 baroreflex activation by CSS significantly reduced blood pressure during control. In contrast, the hypotensive effect was markedly attenuated in Ang II hypertensive dogs. This observation fits very well with today’s understanding of baroreflexes in several forms of hypertension. Remarkably, it is still not fully understood how the autonomic nervous system acts in hypertension, although the issue dates back to the very beginnings of research on cardiovascular reflexes. During that era, it …

Protein kinase C isoforms as specific targets for modulation of vascular smooth muscle function in hypertension

Vascular contraction is an important determinant of the peripheral vascular resistance and blood pressure. The mechanisms underlying vascular smooth muscle (VSM) contraction and the pathological changes that occur in hypertension have been the subject of numerous studies and interpretations. Activation of VSM by vasoconstrictor stimuli at the cell surface causes an increase in [Ca 2+] i, Ca 2+-dependent activation of myosin light chain (MLC) kinase, MLC phosphorylation, actin–myosin interaction and VSM contraction. Additional signaling pathways involving Rho-kinase and protein kinase C (PKC) may increase the myofilament force sensitivity to [Ca 2+] i and MLC phosphorylation, and thereby maintain vascular contraction. PKC is a particularly intriguing protein kinase as it comprises a family of Ca 2+-dependent and Ca 2+-independent isoforms, which have different tissue and subcellular distribution, and undergo differential translocation during cell activation. PKC translocation to the cell surface may trigger a cascade of protein kinases, such as mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK) that ultimately interact with the contractile myofilaments and cause VSM contraction. Also, PKC translocation to the nucleus may promote VSM growth and proliferation. Increased PKC expression and activity have been identified in several forms of hypertension. The subcellular location of PKC may determine the state of VSM activity, and may be useful in the diagnosis/prognosis of hypertension. Vascular PKC isoforms may represent specific targets for modulation of VSM hyperactivity, and isoform-specific PKC inhibitors may be useful in treatment of Ca 2+ antagonist-resistant forms of hypertension.

Comparative assessment of the use of combination options of methyldopa (Aldomet®), Moduretic® and frusemide (Lasix®) in the treatment of hypertensive patients - a Nigerian case study

A total of 80 case-notes of patients who have suffered from mild, moderate and severe forms of hypertension were selected and analyzed. Vital information such as the sex and age of the patients, frequency and length of treatment, adverse reaction and response to treatment were retrieved and recorded. The case-notes selected were those in which tablets of Aldomet®, Moduretic® and Lasix® were used as drugs of choice for the treatment of the hypertension. It was found that the combination of Aldomet® and Moduretic® was more effective in the treatment of hypertension than the combination of Aldomet® and Lasix®. The combination of Aldomet® and Moduretic® was also found to be more effective in males than in females. The pre-treatment blood pressure levels were found to increase with increase in age while the blood pressure levels were significantly affected by the occupations of the patients. Key words: combination option, Aldomet®, Moduretic®, Lasix® antihypertensive Journal of Pharmaceutical and Allied Sciences Vol.2(2) 2005: 197-2001

Expression of mineralocorticoid receptors mRNA in the brain, heart and kidney of Sprague Dawley rats with renovascular hypertension

A large body of evidence indicates that mineralocorticoids play significant role in regulation of cardiovascular functions and in pathogenesis of several forms of hypertension by means of multiple effects exerted in the brain, heart and kidney. However, little is known about regulation of expression of mineralocorticoid receptors mRNA in the hypertensive states. The purpose of the present study was to determine whether expression of mineralocorticoid receptors mRNA is altered in the brain as well as in the left ventricle of the heart and in the kidney in the rats with the Goldblatt 2K,1C renovascular hypertension. Competitive PCR method was used for relative quantitative analysis of mineralocorticoid receptors mRNA in the brain, heart and kidney samples harvested from 12 to 14 weeks old, male Sprague Dawley rats subjected either to constriction of the left renal artery ( n = 8) or to the sham surgery ( n = 9). The 2K,1C rats manifested significantly higher systolic blood pressure ( P < 0.005) and significantly reduced weight of the left kidney ( P < 0.001) in comparison to the sham-operated rats. In both groups, mineralocorticoid receptors mRNA was well expressed in the preoptic, diencephalic, mesencephalopontine, medullary and cerebellar regions of the brain, and in the heart, renal cortex and the renal medulla. Significant differences were found between expression of MR mRNA in different brain regions. In the 2K,1C rats, expression of mineralocorticoid receptors mRNA was significantly lower than in the sham-operated rats in the mesencephalopontine ( P < 0.02) and medullary ( P < 0.005) regions of the brain as well as in the heart ( P < 0.030) and the renal medulla of the kidney ( P < 0.001). No significant differences were detected in the other brain regions and in the renal cortex. The results provide evidence that mineralocorticoid receptors mRNA expression is significantly diminished in the brain stem, the heart and the renal medulla of rats with the 2K,1C renovascular hypertension.

The severe form of hypertension caused by the activating S810L mutation in the mineralocorticoid receptor is cortisone related.

A gain of function mutation resulting in the substitution of leucine for serine at codon 810 (S810L) in the human mineralocorticoid receptor (MR) is responsible for early-onset hypertension that is exacerbated in pregnancy. All steroids, including progesterone, that display antagonist properties when bound to the wild-type MR are able to activate the mutant receptor (MR(L810)). These findings suggest that progesterone may contribute to the dramatic aggravation of hypertension in MR(L810) carriers during pregnancy. However, the steroid(s) responsible for hypertension in MR(L810) carriers (men and nonpregnant women) has not yet been identified. Here we show that cortisone and 11-dehydrocorticosterone, the main cortisol and corticosterone metabolites produced in the distal nephron, where sodium reabsorption stimulated by aldosterone takes place, bind with high affinity to MR(L810). The potency with which cortisone and 11-dehydrocorticosterone bind to the mutant MR contrasts sharply with their low wild-type MR-binding capacity. In addition, cotransfection assays demonstrate that cortisone and 11-dehydrocorticosterone are potent activators of the MR(L810) trans-activation function. Because the plasma concentration of cortisol in humans is about 30-fold higher than that of corticosterone, these findings strongly suggest that cortisone is one of the endogenous steroids responsible for early-onset hypertension in men and nonpregnant women carrying the MR(L810) mutation.

Effect of antihypertensive treatment on small artery remodeling in hypertension.

Blood vessels are remodeled in hypertension both structurally and functionally. The changes that occur in their structure, mechanical properties, and function contribute to blood pressure elevation and to complications of hypertension. We studied the remodeling of small arteries in experimental animals and humans. Smooth muscle cells of small arteries are restructured around a smaller lumen, with significant remodeling of the extracellular matrix and collagen and fibronectin deposition. Interestingly, there is no evidence of net growth of the vascular wall (which results in so-called eutrophic remodeling), particularly in the milder forms of human essential hypertension. Hypertrophic remodeling and increased small artery stiffness may be found in more severe forms of hypertension. Almost all hypertensive patients have vascular structural remodeling. However, only some exhibit endothelial dysfunction. This is particularly true in mild hypertension, in which endothelial dysfunction is less common. A 1-year treatment of hypertensive patients with angiotensin converting enzyme inhibitors, angiotensin AT1 receptor antagonists, and long acting calcium channel blockers corrected small artery structure and, to variable degrees depending on the agents used, impaired endothelial function. In contrast, beta blockers did not improve structure, function, or mechanics of vessels. When beta-blocker-treated patients were switched to an AT1 receptor antagonist, small artery structure and impaired endothelial function were corrected. The vascular protective action of some antihypertensive agents may contribute to improve outcome for hypertensive patients, although this is presently unproven.

Use of Constant Denaturant Capillary Electrophoresis of Pooled Blood Samples to Identify Single-Nucleotide Polymorphisms in the Genes (Scnn1a and Scnn1b) Encoding the α and β Subunits of the Epithelial Sodium Channel

The epithelial sodium channel (ENaC) is composed of three homologous subunits: alpha, beta, and gamma. Mutations in the Scnn1b and Scnn1g genes, which encode the beta and the gamma subunits of ENaC, cause a severe form of hypertension (Liddle syndrome). The contribution of genetic variants within the Scnn1a gene, which codes for the alpha subunit, has not been investigated. We screened for mutations in the COOH termini of the alpha and beta subunits of ENaC. Blood from 184 individuals from 31 families participating in a study on the genetics of hypertension were analyzed. Exons 13 of Scnn1a and Scnn1b, which encode the second transmembrane segment and the COOH termini of alpha- and beta-ENaC, respectively, were amplified from pooled DNA samples of members of each family by PCR. Constant denaturant capillary electrophoresis (CDCE) was used to detect mutations in PCR products of the pooled DNA samples. The detection limit of CDCE for ENaC variants was 1%, indicating that all members of any family or up to 100 individuals can be analyzed in one CDCE run. CDCE profiles of the COOH terminus of alpha-ENaC in pooled family members showed that the 31 families belonged to four groups and identified families with genetic variants. Using this approach, we analyzed 31 rather than 184 samples. Individual CDCE analysis of members from families with different pooled CDCE profiles revealed five genotypes containing 1853G-->T and 1987A-->G polymorphisms. The presence of the mutations was confirmed by DNA sequencing. For the COOH terminus of beta-ENaC, only one family showed a different CDCE profile. Two members of this family (n = 5) were heterozygous at 1781C-->T (T594M). CDCE rapidly detects point mutations in these candidate disease genes.

Genetics of the mineralocorticoid system in primary hypertension.

Abnormalities in steroid biosynthesis have been known for years to cause hypertension in some cases of congenital adrenal hyperplasia. In these patients hypertension usually accompanies a characteristic phenotype with abnormal sexual differentiation. Recently, the molecular basis of four forms of severe hypertension transmitted on an autosomal basis but without additional phenotypic features has been elucidated. All these conditions are characterized primarily by low plasma renin, normal or low serum potassium, and salt-sensitive hypertension, indicating an increased mineralocorticoid effect. These four disorders, the glucocorticoid remediable aldosteronism, the syndrome of apparent mineralocorticoid excess, the activating mutation of the mineralocorticoid receptor, and the Liddle syndrome are a consequence of either abnormal biosynthesis, metabolism, or action of steroid hormones, and are ultimately characterized by an overactivation of the epithelial sodium channel in distal renal tubules. Hyperactivity of this channel results in increased sodium reabsorption and volume expansion leading to an increase in blood pressure as well as potassium loss. With the advent of molecular biology in clinical practice, it has become evident that some genetic defect may present with a more discrete phenotype, with only moderate hypertension with or without hypokalemia as the sole feature. A search for genetic disorders of the mineralocorticoid axis should be an integral part of the diagnostic work-up, particularly in young adults with hypertension.

Blood Pressure Control and Benefits of Antihypertensive Therapy

This article debates the important question of whether blood pressure lowering alone is responsible for the benefits accrued from antihypertensive therapy as demonstrated in many multicenter randomized clinical trials with different antihypertensive agents or whether there is evidence that some agents have special properties that result in benefits that go beyond those resulting from lowering blood pressure. Over the past >/=30 years, it has been demonstrated beyond any doubt that lowering blood pressure in severe forms of hypertension, and more recently in systolic and even mild hypertension, will result in reduced incidence of stroke and slower progression of heart and renal failure. These effects have been easier to demonstrate in sicker patients, because enough end points may be counted in the 3 to 5 years that these clinical trials last. However, risk attributable to high blood pressure comes, to a greater degree, from the much larger group of hypertensive individuals who have less severe forms of hypertension. Blood pressure lowering offers less protection from coronary heart disease, which is highly prevalent in hypertensive patients, than from stroke. With the introduction of agents such as renin-angiotensin system inhibitors or calcium channel blockers, it has been demonstrated that hypertensive vascular remodeling and endothelial dysfunction may be corrected. It has therefore been suggested that benefits beyond blood pressure lowering may be achieved with the use of specific drugs to lower blood pressure. Although some evidence suggests that this may be the case, it is difficult to extrapolate from mechanistic studies to prevention of hard end points in outcome trials and vice versa. The question remains for the time being largely unanswered.

Ovarian hormones modulate endothelin-1 vascular reactivity and mRNA expression in DOCA-salt hypertensive rats.

We previously demonstrated a differential activation of the endothelin-1 (ET-1) pathway in male and female deoxycorticosterone (DOCA)-salt hypertensive rats, with the male rats exhibiting marked alterations in vascular and pressor responses to ET-1 and Suc-[Glu,(9)Ala(11,15)]-ET-1(8-21) (IRL-1620), an ET(B) agonist. Mechanisms underlying these gender differences are unclear, and we hypothesized that the ovarian hormones attenuate vascular ET(B) responses in female DOCA-salt rats. Female Wistar rats were randomized in 3 groups: sham-operated, ovariectomized (OVX), and OVX plus hormone replacement with estradiol (E) or estradiol/progesterone (EP). Two weeks later, rats were uninephrectomized and further randomized in DOCA-salt (subcutaneous injections of desoxycorticosterone and drinking water containing NaCl/KCl) and control normotensive (subcutaneous injections of vehicle and tap water). Blood pressure was evaluated both by direct and standard tail-cuff methods. Responses to IRL-1620 were evaluated in vivo/in situ in the mesenteric microcirculation. mRNA expression of ET-1 and ET(A/B) receptors was evaluated in mesenteric arteries by reverse transcription-polymerase chain reaction and expressed relative to GAPDH. OVX-DOCA rats developed a more severe form of hypertension than did DOCA rats. Treatment with E or EP restored blood pressure to levels observed in DOCA rats. In the mesentery, IRL-1620 induced vasodilatation in control rats, a mild vasoconstriction in DOCA rats, and marked vasoconstriction in OVX-DOCA rats. Both E and EP decreased IRL-1620-induced vasoconstriction in the DOCA group. In the normotensive group, OVX did not change blood pressure or IRL-1620-induced vasodilation. Removal of the ovaries increased ET-1 mRNA in arteries from DOCA and control rats, although treatment with E or EP reversed these changes. Vascular ET(B) receptor mRNA levels were greatly enhanced in OVX-DOCA but not OVX-control rats. Hormone replacement with E or EP restored ET(B) receptor expression in the DOCA group. A greater blood pressure-lowering effect of bosentan (ET(A)/ET(B) blocker) was observed in OVX-DOCA rats. The observation that OVX worsens hypertension as well as the altered ET(B) receptor-mediated responses and the effects of bosentan in female DOCA rats supports our suggestion that the ovarian hormones modulate ET-1/ET(B) receptor vascular responses/expression in DOCA-salt hypertension.

Dyslipidaemia in patients with malignant-phase hypertension.

Low-density lipoprotein (LDL) consists of a heterogeneous group of particles of differing size, density and electrophoretic mobility, smaller particles being more atherogenic. A high proportion of small LDL particles is an independent risk factor for cardiovascular disease. We hypothesized that patients with malignant phase hypertension (MHT), the most severe form of hypertension, would demonstrate a more atherogenic LDL subfraction profile than either non-malignant hypertension (NMHT) or normotensive controls. We compared 16 patients with MHT to 41 patients with untreated NMHT and 45 normotensive controls. LDL subfraction profile was measured by disc polyacrylamide gel electrophoresis using a validated scoring system to calculate the mean size (locus) and heterogeneity (spread) of LDL subfraction mobilities. A higher LDL locus indicates a greater proportion of small LDL subfractions. LDL cholesterol levels were similar in all three groups (p=0.23). High-density lipoprotein cholesterol (HDL-C) levels were significantly lower (p<0.001) and serum triglyceride concentrations significantly higher (p=0.02) in the MHT group, compared to normotensive controls. LDL locus was greater in the NMHT group than in the normotensive controls and intermediate in the MHT group (p=0.008). There was no significant difference in LDL spread (p=0.26). Serum triglyceride concentrations were not significantly higher after adjusting for confounding variables. MHT is associated with an abnormal lipid profile, characterized by low HDL-cholesterol concentration. This dyslipidaemia may be partly responsible for the vascular complications and the poor prognosis of these patients.

Recombinant CRP induces increased release of ICAM and thrombomodulin, but not vWF or E selectin, from HUVECs

The activation of Ca2+-dependent K+ channels (BKCa) leads to the attenuation of vascular contraction. Our study aimed to evaluate BKCa influence on norepinephrine (NE)-induced femoral artery contraction in two forms of genetic hypertension. NE dose-response curves were studied before and after BKCa blockade or after combined blockade of BKCa and NO synthase (NOS) in femoral arteries with intact endothelium from normotensive Wistar (WIS), hypertensive hereditary hypertriglyceridemic (HTG), or spontaneously hypertensive rats (SHR). NE-induced contractions of femoral arteries were augmented in both hypertensive strains compared with Wistar rats, but acetylcholine-induced relaxation was impaired in HTG only. The increase of basal vascular tone of isolated arteries after BKCa blockade was similar in all rat strains, but subsequent NOS inhibition increased basal vascular tone more in vessels from both hypertensive rat strains. NOS inhibition increased sensitivity to NE in all strains, but BKCa blockade in SHR only. Neither treatment enhanced maximal NE-induced contraction. NO-dependent attenuation of NE-induced contractions was greater in SHR than HTG or Wistar vessels, whereas large conductance Ca2+-dependent K+ channels may play a greater role in modulating vascular contraction in the severe form of hypertension.

Do patients with de novo hypertension differ from patients with previously known hypertension when malignant phase hypertension occurs?

Malignant phase hypertension (MHT) represents the most severe form of hypertension, and many consider that this condition only occurs in poorly managed patients with previously known hypertension. To investigate this further, we studied 350 patients with MHT on the West Birmingham MHT database: 195 (55.7%) of these presented de novo, without any known past history of hypertension (Group 1), and 146 (41.7%) were previously known hypertensives (Group 2), of whom 86 were receiving antihypertensive therapy; in 9 patients, the status was uncertain. Median duration of clinical followup was similar in both groups (36.0 v 37.5 months, Mann-Whitney test P = .795). Patients presenting de novo with MHT (Group 1) were younger, with a predominance of whites and men. Nevertheless, the clinical features, blood pressures, and renal function at presentation were similar to MHT patients with previously known hypertension. Renal function at follow-up was also similar in both groups. There was an excess of women and nonwhites in MHT patients with previously known hypertension (Group 2), who also had higher mean follow-up blood pressures. On univariate life-table analysis, there was no statistically significant difference in survival time between Groups 1 and 2 (mean 57.5 v 63.5 months, median 36.0 v 37.0 months; log-rank test, P = .456). Using a multivariate Cox analysis of baseline variables, the independent predictors of outcome (death or dialysis) were age at presentation ( P = .0019), diastolic blood pressure ( P = .0466), serum urea ( P = .006), and serum creatinine ( P < .001). Whether the patient had presented de novo, without any known history of hypertension (Group 1) or had previously known hypertension (Group 2) did not independently predict outcome ( P = .6549). We suggest that MHT can occur de novo in patients without previously known hypertension, and the clinical characteristics and prognosis in such patients were similar to MHT patients with previously known hypertension.

Antihypertensive effect of a compound (PST 2238) that displaces ouabain from sodium pump in experimental hypertension

A major biologically active Na,K-ATPase inhibitor in the mammalian body may be ouabain-like compound (OLC). We investigated the contribution of OLC to high blood pressure (BP) in reduced renal mass-saline hypertension as a classical model of sodium-dependent hypertension. We used PST 2238 (PST), an orally active antiouabain agent, to block the action of OLC. First, the antihypertensive effect was examined in ouabain-induced hypertensive rats to confirm the antagonistic action of PST (10 mg/kg/day) against ouabain in vivo. Second, we tested the effect of PST in comparison with potassium canrenoate (100 mg/kg/day) on BP in established reduced renal mass (5/6)-saline hypertension in rats. Potassium canrenoate has been supposed to act partially as an ouabain antagonist and was used as a reference drug. Third, we compared the antihypertensive effect of PST on established reduced renal mass (4/6)-saline hypertension with those of potassium canrenoate and doxazosin mesylate (2 mg/kg/day). The continuous ouabain (100 μg/kg/day) infusion with osmotic minipump elevated BP after 4 weeks and a concomitant treatment with PST for 4 weeks abolished this rise in BP (P < 0.01). In rats with severe reduced renal mass-saline hypertension, PST administration for 2 weeks lowered BP (P < 0.01) to the same degree as potassium canrenoate. Also in rats with less severe reduced renal mass-saline hypertension, PST administration for 4 weeks reduced BP (P < 0.01) to the same degree as potassium canrenoate and doxazosin mesylate. These findings suggest that OLC may contribute to the elevated BP in reduced renal mass-saline hypertension and that PST may be an effective antihypertensive agent in several forms of hypertension characterized by increased OLC levels.

Malignant phase hypertension is associated with abnormalities of low density lipoprotein subfraction profiles

Elevated levels of low density lipoprotein (LDL) are an independent risk factor for cardiovascular disease. LDL however is not a single entity but consists of a heterogeneous group of particles with smaller dense particles being the most atherogenic. To test the hypothesis that malignant hypertension (MHT), the most severe form of hypertension, is associated with an abnormal lipid profile, and that this may contribute to the complications of MHT, we studied 18 patients presenting with this condition (49.4 (11.4) years; 16 male; 236/141). LDL subfraction profile was measured by disc polyacrylamide gel electrophoresis using a validated scoring system to calculate the mean (locus) and standard deviation (spread) mobility of LDL. Results were compared with 41 patients with non-malignant, untreated hypertension (mean age 53.9 years; 24 male systolic/diastolic blood pressure 173/100) and 45 normotensive patients with normal coronary angiograms (58 (10.6) years; 22 male; 136/80).

The role of the 11β-hydroxysteroid dehydrogenase type 2 in human hypertension

The 11 beta-hydroxysteroid dehydrogenase type 2 (11 PHSD2) enzyme inactivates 11 betahydroxy steroids in sodium-transporting epithelia such as the kidney, thus protecting the non-selective mineralocorticoid receptor (MR) from occupation by cortisol in humans. Inhibition by xenobiotics such as liquorice or mutations in the HSD11 B2 gene, as occur in the rare monogenic hypertensive syndrome of apparent mineralocorticoid excess (AME), result in a compromised 11 betaHSD2 enzyme activity, which in turn leads to overstimulation of the MR by cortisol, sodium retention, hypokalaemia, low plasma renin and aldosterone concentrations, and hypertension. Whereas the first patients described with AME had a severe form of hypertension and metabolic derangements, with an increased urinary ratio of cortisol (THF+5alphaTHF) to cortisone (THE) metabolites, more subtle effects of mild 11 beta HSD2 deficiency on blood pressure have recently been observed. Hypertension with no other characteristic signs of AME was found in the heterozygous father of a child with AME, and we described a girl with a homozygous gene mutation resulting in only a slightly reduced 11 beta HSD2 activity causing 'essential' hypertension. Thus, depending on the degree of loss of enzyme activity, 11 beta HSD2 mutations can cause a spectrum of phenotypes ranging from severe, life-threatening hypertension in infancy to a milder form of the disease in adults. Patients with essential hypertension usually do not have overt signs of mineralocorticoid excess, but nevertheless show a positive correlation between blood pressure and serum sodium levels, or a negative correlation with potassium concentrations, suggesting a mineralocorticoid influence. Recent studies revealed a prolonged half-life of cortisol and an increased ratio of urinary cortisol to cortisone metabolites in some patients with essential hypertension. These abnormalities may be genetically determined. A genetic association of a HSD11 B2 flanking microsatellite and hypertension in black patients with end-stage renal disease has been reported. A recent analysis of a CA-repeat allele polymorphism in unselected patients with essential hypertension did not find a correlation between this marker and blood pressure. Since steroid hormones with mineralocorticoid action modulate renal sodium retention, one might hypothesize that genetic impairment of 11 beta HSD2 activity would be more prevalent in salt-sensitive as compared with salt-resistant subjects. Accordingly, we found a significant association between the polymorphic CA-microsatellite marker and salt-sensitivity. Moreover, the mean ratio of urinary cortisol to cortisone metabolites, as a measure for 11betaHSD2 activity, was markedly elevated in salt-sensitive subjects. These findings suggest that variants of the HSD11 B2 gene may contribute to the enhanced blood pressure response to salt in some humans.

Parathyroid hypertensive factor inhibits voltage-gated K+ channels in vascular smooth muscle cells

Parathyroid hypertensive factor (PHF) has been implicated in regulation of vascular smooth muscle tone and pathogenesis of several forms of hypertension. Earlier studies have suggested that PHF enhances the actions of other vasoconstrictors, while it has no in vitro vasoconstrictor property of its own. PHF was previously found to enhance the L-type Ca channel currents and intracellular Ca responses to depolarization in vascular smooth muscle cells (VSMCs). The present study examined whether PHF might act on K channels in the plasma membrane of VSMCs. Primary cultured VSMCs from rat tail artery were used. The whole-cell version of the patch-clamp technique was used under conditions in which there was no contribution of Ca-activated K channels to the outward current. Both purified and semipurified PHF inhibited the delayed rectifier type potassium current in a dose-dependent manner. The effect was time dependent and was first significantly different from the control current after 30 min. The inhibition of the delayed rectifier K channel was associated with a time-dependent decrease in the resting membrane potential. Therefore, PHF may alter VSMC cellular Ca responses by reducing the membrane potential to a level closer to the activation potential of Ca channels.