Methyclothiazide Research Articles

Direct vascular actions of methyclothiazide in remodeled mesenteric arteries from hypertensive patients

In vitro experiments were designed to assess the inhibitory effect of the thiazide diuretic methyclothiazide (MCTZ) on contractile responses to norepinephrine (NE) of mesenteric rings from hypertensive patients and normotensive controls. Arteries were taken from portions of mesocolon from 24 patients: 13 hypertensives and 11 normotensives. Changes in the tension of mesenteric ring preparations were measured isometrically. Histologic studies showed that the arteries from hypertensive patients exhibited 1) a greater media thickness-to-lumen diameter ratio, 2) a smaller lumen diameter, and 3) identical media cross-sectional area as those of normotensive controls. At the physiologic level, the hypertensive and normotensive arteries display similar contractile responses to KCl and NE. Furthermore, our results indicate that MCTZ induces concentration-dependent inhibition of the vasoconstrictor responses to NE. This study provides evidence that hypertension is associated with the remodeling of the human mesenteric artery and that MCTZ is as efficient in inhibiting the contractile response induced by NE on hypertensive than on normotensive arteries.

Mechanisms of methyclothiazide-induced inhibition of contractile responses in rat aorta

Methyclothiazide (MCTZ), a thiazide diuretic, inhibits the contractile response induced by norepinephrine in aortic rings from 12-week-old spontaneously hypertensive rats (SHR). Although not modified by indomethacin, this inhibition was attenuated by either mechanical removal of the endothelium or Nω-nitro- l-arginine (NOLA) treatment. These results suggest that the MCTZ effects on the norepinephrine-evoked vascular response are mediated by an endothelium-dependent mechanism involving endothelium-dependent relaxing factor (EDRF)/nitric oxide (NO) release. MCTZ was also found to alter the contractile response induced by the addition of Ca 2+ to a depolarizing solution, and this inhibitory effect was partially abolished by NOLA application. Our data led us to propose that MCTZ relaxes aortic rings, resulting in an endothelium-dependent relaxation phenomenon that could even be reinforced under high-K + depolarizing conditions.

Direct vascular actions of methyclothiazide and indapamide in aorta of spontaneously hypertensive rats

In vitro experiments were designed to assess the inhibitory effect of the thiazide diuretics methyclothiazide (MCTZ), the hydrochlorothiazide (HCTZ), and the thiazide-related diuretic indapamide (IND) on contractile responses to norepinephrine (NE) and arginine vasopressin (AVP) of aortic rings from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Changes in the tension of aortic ring preparations were measured isometrically. MCTZ (10(-4) M) induced endothelium-dependent inhibition of the vasoconstrictor responses to NE and AVP only in aortas from SHR, and the maximal vasoconstrictive effect of NE and AVP was decreased by 59 +/- 11% and 32.3 +/- 13%, respectively. Indapamide (10(-4) M) also induced endothelium-dependent inhibition of the contractile response to AVP in aortic rings from SHR, and the maximal vasoconstrictive effect of AVP was decreased by 33 +/- 5%. In contrast, HCTZ did not inhibit the contractile response to either NE or AVP, even at the highest concentration. This study provides evidence that methyclothiazide and indapamide inhibit the contractile response induced by norepinephrine and/or arginine vasopressin on SHR aortic preparations via an endothelium-dependent mechanism.

The effects of terazosin and methyclothiazide on blood pressure and serum lipids

This study compared the antihypertensive efficacy and the effects on serum lipids of terazosin, a new selective α 1-adrenergic antagonist, of methyclothiazide (MCTZ), and of the two drugs used as combination therapy. Adult patients with supine diastolic blood pressures ranging from 95 to 120 mm Hg were eligible to enter this double-blind, randomized, parallel-group study. Analyses of the blood pressure data from the 194 evaluable patients revealed that all three treatments produced significant ( p < 0.001) reductions in supine and standing systolic and diastolic blood pressures from baseline values. Moreover, combination therapy resulted in significantly greater mean blood pressure reductions than were observed with either drug used as monotherapy. In the group receiving terazosin monotherapy, the total serum cholesterol level, low-density lipoprotein plus very-low-density lipoprotein cholesterol fraction, and triglyceride level fell significantly (median changes of 3.7%, 5.0%, and 16.3%, respectively, p < 0.05). However, in the group receiving MCTZ monotherapy, the total serum cholesterol level, low-density lipoprotein plus very-low-density lipoprotein cholesterol fraction, and triglyceride level increased significantly (4.7%, 7.1%, and 12.5%, respectively, p < 0.001). In contrast, no significant changes from baseline values were observed for any lipid variable in the group receiving terazosin/MCTZ combination therapy. We conclude that terazosin is effective antihypertensive therapy that has a potentially beneficial effect on the serum lipid profile when used as monotherapy and that it counteracts the negative impact of MCTZ monotherapy on the serum lipid profile when used concurrently with this thiazide diuretic.

UV-A induced DNA nicking activities of skin photosensitive drugs: Phenothiazines, benzothiadiazines and afloqualone

Plasmid pBR 322 was subjected to UV-A irradiation in the presence of photosensitive drugs, i.e., phenothiazines [chlorpromazine hydrochloride (CPZ), promethazine hydrochloride (PMZ) and mequitazine (MQZ)], benzothiadiazines [penflutizide (PFZ), hydrochlorothiazide (HCT) and methyclothiazide (MCT)] and afloqualone (AQ). The distribution of the closed-circular and the open-circular form of the plasmid DNA was analyzed by means of neutral agarose gel electrophoresis. All the drugs used induced more or less DNA nicking to yield the open-circular form. The nicking activities of the phenothiazines were in the order: CPZ>PMZ>MQZ. CPZ elicited extensive degradation of the DNA by photosensitization. The nicking activities of the benzothiadiazines and AQ were much weaker than CPZ and PMZ.

A Double-Blind Controlled Study on the Antihypertensive Effectiveness of Uricosu-ric Diuretic FR 3068 in Essential Hypertension as Compared with Methyclothiazide

The antihypertensive effectiveness, influence on laboratory parameters and adverse reaction of FR 3068 (tienilic acid, FR), a new nonthiazide diuretic developed by Albert Rolland Co. of France with uricosuric properties, were evaluated by double-blind parallel group comparison with methyclothiazide (MCTZ).Placebo was initially administered for a period of at least 2 weeks. Patients with systolic blood pressure of≥150 mHg and diastolic blood pressure of≥90 mmHg at the termination of the placebo control period were enrolled as subjects .FR and MCTZ were administered in fixed dosages of 250 mg/day and 5 mg/day respectively. The duration of treatmentwas 8 weeks.Blood pressure significantly decreased in both groups in 2 weeks. In MCTZ group, blood pressure showed a continuous, gradual decrease until Week 8. In FR group, a mild reduction in blood pressure was seen from Week 2 onwards, at Week 8 there being a further decrease.Comparison of laboratory data before and after treatment revealed increase in BUN and serum Na+ in FR group.In MCTZ group, increase in some hematological indexes and serum creatinine value and decrease in serum Na+, K+ and Cl- were seen. Severe liver function disturbance was noted in one patient of FR group.Serum uric acid increased in MCTZ group.In contrast, it decreased in FR demonstrating a distinct uricosuric effect.Symptoms appearing during the treatment period which did not occur during the control period consisted of those of central nervous, autonomic nervous and gastrointestinal systems. These symptoms occurred in 15 of 50 patients in the FR group and 7 of 46 patients in the MCTZ group.The usefulness of both drugs was globally assessed based on symptomatic change, antihypertensive effectiveness, adverse reaction, laboratory data abnormalities, etc. There was no significant intergroup difference at 5% level.

利尿剤に関する研究(第5報)

The diuretic effects of hypotensive diuretics in spontaneously hypertensive rats (SHR) were compared to that of normal rats (NR). Furthermore, the combination effect in SHR and NR was studied. The following results were obtained; (1) SHR had most favorable and stronger sensitivity with hydroflumethiazide (HFT) administration. (2) SHR had a stronger sensitivity on the potassium sparing effect of triamterene (TAT). (3) SHR had also strong sensitivity on the diuretic effects of methyclothiazide (MCT), hydrochlorothiazide (HCT), furosemide (Fur) and clorexolone (Clo) which are potent in NR. (4) In SHR, spironolactone (SPL) showed dose-dependent saluresis which was simultaneously accompanied with kaliuresis. (5) In SHR, mercaptomerine and aminophylline had no diuretic effect. (6) In NR, combining MCT, HFT, HCT and acetazolamide (ACT) to TAT, all cases showed synergism. (7) In SHR, combining MCT, HFT, and HCT to TAT, a more excellent synergism was seen than in NR. Particularly, a combination of TAT and HFT resulted in the highest Na+/K+ excretion ratio. (8) In NR, combinig MCT, HFT and HCT to SPL, weak synergism was seen. (9) Combination MCT to SPL showed little synergism in SHR. (10) When ACT was combined with TAT or SPL in SHR, the diuretic effect decreased more than in a single administration.