tram-34 and Hypertension

Increasing evidence confirms that potassium channels are essential for lymphocyte activation, suggesting an involvement in the development of hypertension. Moreover, chronic inflammation is regarded as a direct or indirect manifestation of hypertension, highlighting the theoretical mechanisms. In this study, we investigated changes in KCa3.1 potassium channel expression in the blood of hypertensive and healthy Kazakh people in north-west China.. Flow cytometry technology was used for T-lymphocyte subtype analysis. Changes in the messenger RNA and protein expression of the KCa3.1 potassium channel in CD4. Expression of KCa3.1 was significantly higher in the hypertensive patients than in the controls (p < 0.05). Compared with the healthy group, Kazakh hypertensive patients had a reduced proportion of CD4. Increase in functional KCa3.1 channels expressed in CD4

Topics: Adult; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Case-Control Studies; CD4-Positive T-Lymphocytes; Cell Culture Techniques; Cell Proliferation; China; Female; Humans; Hypertension; Intermediate-Conductance Calcium-Activated Potassium Channels; Kazakhstan; Kv1.3 Potassium Channel; Male; Middle Aged; Protein Biosynthesis; Pyrazoles; RNA, Messenger; Tetrazoles; Transcription, Genetic

The calcium-activated potassium channel KCa3.1 is expressed in the vascular endothelium where its activation causes endothelial hyperpolarization and initiates endothelium-derived hyperpolarization (EDH)-dependent dilatation. Here, we investigated whether pharmacological activation of KCa3.1 dilates skeletal muscle arterioles and whether myoendothelial gap junctions formed by connexin40 (Cx40) are required for EDH-type dilatations and pressure depressor responses in vivo.. We performed intravital microscopy in the cremaster muscle microcirculation and blood pressure telemetry in Cx40-deficient mice.. In wild-type mice, the KCa3.1-activator SKA-31 induced pronounced concentration-dependent arteriolar EDH-type dilatations, amounting to ∼40% of maximal dilatation, and enhanced the effects of ACh. These responses were absent in mice devoid of KCa3.1 channels. In contrast, SKA-31-induced dilatations were not attenuated in mice with endothelial cells deficient in Cx40 (Cx40(fl/fl):Tie2-Cre). In isolated endothelial cell clusters, SKA-31 induced hyperpolarizations of similar magnitudes (by ∼38 mV) in Cx40(fl/fl):Tie2-Cre, ubiquitous Cx40-deficient mice (Cx40(-/-)) and controls (Cx40(fl/fl)), which were reversed by the specific KCa3.1-blocker TRAM-34. In normotensive wild-type and Cx40(fl/fl):Tie2-Cre as well as in hypertensive Cx40(-/-) animals, i.p. injections of SKA-31 (30 and 100 mg·kg(-1)) decreased arterial pressure by ∼32 mmHg in all genotypes. The depressor response to 100 mg·kg(-1) SKA-31 was associated with a decrease in heart rate.. We conclude that endothelial hyperpolarization evoked by pharmacological activation of KCa3.1 channels induces EDH-type arteriolar dilatations that are independent of endothelial Cx40 and Cx40-containing myoendothelial gap junctions. As SKA-31 reduced blood pressure in hypertensive Cx40-deficient mice, KCa3.1 activators may be useful drugs for severe treatment-resistant hypertension.

Topics: Animals; Benzothiazoles; Blood Pressure; Connexins; Dose-Response Relationship, Drug; Endothelial Cells; Endothelium, Vascular; Gap Junction alpha-5 Protein; Gap Junctions; Genotype; Heart Rate; Hypertension; Intermediate-Conductance Calcium-Activated Potassium Channels; Mice; Mice, Knockout; Microcirculation; Pyrazoles; Telemetry; Vasodilation

Maternal undernutrition results in elevated blood pressure (BP) and endothelial dysfunction in adult offspring. However, few studies have investigated interventions during early life to ameliorate the programming of hypertension and vascular disorders. We have utilised a model of maternal undernutrition to examine the effects of pre-weaning growth hormone (GH) treatment on BP and vascular function in adulthood. Female Sprague-Dawley rats were fed either a standard control diet (CON) or 50% of CON intake throughout pregnancy (UN). From neonatal day 3 until weaning (day 21), CON and UN pups received either saline (CON-S, UN-S) or GH (2.5 ug/g/day)(CON-GH, UN-GH). All dams were fed ad libitum throughout lactation. Male offspring were fed a standard diet until the end of the study. Systolic blood pressure (SBP) was measured at day 150 by tail cuff plethysmography. At day 160, intact mesenteric vessels mounted on a pressure myograph. Responses to pressure, agonist-induced constriction and endothelium-dependent vasodilators were investigated to determine vascular function. SBP was increased in UN-S groups and normalised in UN-GH groups (CON-S 121±2 mmHg, CON-GH 115±3, UN-S 146±3, UN-GH 127±2). Pressure mediated dilation was reduced in UN-S offspring and normalised in UN-GH groups. Vessels from UN-S offspring demonstrated a reduced constrictor response to phenylephrine and reduced vasodilator response to acetylcholine (ACh). Furthermore, UN-S offspring vessels displayed a reduced vasodilator response in the presence of L-NG-Nitroarginine Methyl Ester (L-NAME), carbenoxolone (CBX), L-NAME and CBX, Tram-34 and Apamin. UN-GH vessels showed little difference in responses when compared to CON and significantly increased vasodilator responses when compared to UN-S offspring. Pre-weaning GH treatment reverses the negative effects of maternal UN on SBP and vasomotor function in adult offspring. These data suggest that developmental cardiovascular programming is potentially reversible by early life GH treatment and that GH can reverse the vascular adaptations resulting from maternal undernutrition.

Topics: Acetylcholine; Adult; Animals; Apamin; Blood Pressure; Carbenoxolone; Female; Growth Hormone; Humans; Hypertension; Male; Malnutrition; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Phenylephrine; Pregnancy; Pyrazoles; Rats; Rats, Sprague-Dawley; Time Factors; Vasoconstriction; Vasodilation; Weaning

β-Adrenoceptor (β-AR)-mediated relaxation plays an important role in the regulation of vascular tone. β-AR-mediated vascular relaxation is reduced in various disease states and aging. We hypothesized that β-AR-mediated vasodilatation is impaired in DOCA-salt hypertension due to alterations in the cAMP pathway. β-AR-mediated relaxation was determined in small mesenteric arteries from DOCA-salt hypertensive and control uninephrectomized (Uni) rats. To exclude nitric oxide (NO) and cyclooxygenase (COX) pathways, relaxation responses were determined in the presence of l-NNA and indomethacin, NO synthase inhibitor and COX inhibitors, respectively. Isoprenaline (ISO)-induced relaxation was reduced in arteries from DOCA-salt compared to Uni rats. Protein kinase A (PKA) inhibitors (H89 or Rp-cAMPS) or adenylyl cyclase inhibitor (SQ22536) did not abolish the difference in ISO-induced relaxation between the groups. Forskolin (adenylyl cyclase activator)-induced relaxation was similar between the groups. The inhibition of IK(Ca)/SK(Ca) channels (TRAM-34 plus UCL1684) or BK(Ca) channels (iberiotoxin) reduced ISO-induced relaxation only in Uni rats and abolished the relaxation differences between the groups. The expression of SK(Ca) channel was decreased in DOCA-salt arteries. The expression of BK(Ca) channel α subunit was increased whereas the expression of BK(Ca) channel β subunit was decreased in DOCA-salt arteries. The expression of receptor for activated C kinase 1 (RACK1), which is a binding protein for BK(Ca) channel and negatively modulates its activity, was increased in DOCA-salt arteries. These results suggest that the impairment of β-AR-mediated relaxation in DOCA-salt mesenteric arteries may be attributable to altered IK(Ca)/SK(Ca) and/or BK(Ca) channels activities rather than cAMP/PKA pathway. Impaired β-AR-stimulated BK(Ca) channel activity may be due to the imbalance between its subunit expressions and RACK1 upregulation.

Topics: Adrenergic beta-Agonists; Alkanes; Animals; Desoxycorticosterone; GTP-Binding Proteins; Hypertension; Isoproterenol; Male; Mesenteric Arteries; Peptides; Potassium Channels, Calcium-Activated; Pyrazoles; Quinolinium Compounds; Rats; Rats, Wistar; Receptors for Activated C Kinase; Receptors, Adrenergic, beta; Signal Transduction; Sodium Chloride; Vasodilation

The purpose of the study was to investigate renal endothelium-dependent vasodilatation in a model of severe hypertension associated with kidney injury.. Changes in perfusion pressure were measured in isolated, perfused kidneys taken from 18-week-old Wistar-Kyoto rat (WKY), spontaneously hypertensive rats (SHR) and SHR treated for 2 weeks with N(ω) -nitro-L-arginine methyl ester in the drinking water (L-NAME-treated SHR, 6 mg·kg(-1) ·day(-1) ).. Acetylcholine caused similar dose-dependent renal dilatation in the three groups. In vitro administration of indomethacin did not alter the vasodilatation, while the addition of N(w) -nitro-L-arginine (L-NA) produced a differential inhibition of the vasodilatation, (inhibition in WKY > SHR > L-NAME-treated SHR). Further addition of ODQ, an inhibitor of soluble guanylyl cyclase, abolished the responses to sodium nitroprusside but did not affect the vasodilatation to acetylcholine. However, the addition of TRAM-34 (or charybdotoxin) inhibitors of Ca(2+) -activated K(+) channels of intermediate conductance (K(Ca) 3.1), blocked the vasodilatation to acetylcholine, while apamin, an inhibitor of Ca(2+) -activated K(+) channels of small conductance (K(Ca) 2.3), was ineffective. Dilatation induced by an opener of K(Ca) 3.1/K(Ca) 2.3 channels, NS-309, was also blocked by TRAM-34, but not by apamin. The magnitude and duration of NS-309-induced vasodilatation and the renal expression of mRNA for K(Ca) 3.1, but not K(Ca) 2.3, channels followed the same ranking order (WKY < SHR < L-NAME-treated SHR).. In SHR kidneys, an EDHF-mediated response, involving activation of K(Ca) 3.1 channels, contributed to the mechanism of endothelium-dependent vasodilatation. In kidneys from L-NAME-treated SHR, up-regulation of this pathway fully compensated for the decrease in NO availability.

Topics: Acetylcholine; Animals; Apamin; Biological Factors; Endothelium, Vascular; Enzyme Inhibitors; Hypertension; In Vitro Techniques; Indoles; Indomethacin; Intermediate-Conductance Calcium-Activated Potassium Channels; Kidney; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroarginine; Nitroprusside; Oximes; Potassium Channel Blockers; Pyrazoles; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasodilation; Vasodilator Agents