Disease relevance of Pinacidil anhydrous

• KATP channels are important regulators of secretory processes and muscle contraction, and are targets for therapeutic treatment of type II diabetes by the inhibitory sulphonylureas and for hypertension by activators such as pinacidil [1].
• Unanticipated lessening of the rise in extracellular potassium during ischemia by pinacidil [2].
• BACKGROUND: The activation of ATP-sensitive K+ (K+ ATP) channels by K+ ATP openers, eg, pinacidil, hypoxia, and ischemia, is known to shorten the ventricular action potential [3].
• Intravenous Cs+ (total dose, 4.5 mM/kg) was used to produce ventricular arrhythmias in anesthetized rabbits randomly pretreated in a double-blind fashion with either low-dose pinacidil (0.2 mg/kg) or vehicle [4].
• Hearts treated with pinacidil demonstrated a rapid recovery of a coordinated contraction pattern, which was offset by a reperfusion tachycardia, whereas PDBu arrest was associated with ventricular fibrillation on reperfusion [5].

Psychiatry related information on Pinacidil anhydrous

• Diazoxide and pinacidil, two ATP-sensitive K(+) channel openers, injected by intraplantar route, induced a long-lasting increment of pain threshold of the animals and produced antinociception in both models of hyperalgesia [6].
• The potential of ATP-sensitive potassium channel openers (KCOs) for the treatment of male erectile dysfunction has recently been suggested based on positive clinical outcomes following intra-cavernosal administration of pinacidil [7].
• After two weeks of treatment with 17-beta-estradiol, pinacidil failed to significantly decrease heart rate in males however, tamoxifen-pretreated female group responded by decrease in automatism in the presence of rising concentration of pinacidil (Emax=-45+/-6 bpm, not significantly different from Emax in male control=-40+/-5 bpm, n=7) [8].

High impact information on Pinacidil anhydrous

• The K(+) channel opener pinacidil did not induce K(+) currents in vascular smooth-muscle cells of Kir6.1-null mice, and there was no vasodilation response to pinacidil [9].
• Glibenclamide, a K(ATP) channel inhibitor, and DL-propargylglycine, a CSE inhibitor, exacerbated, whereas pinacidil, a K(ATP) opener, attenuated gastric injury caused by ASA [10].
• Cotransfection with Kir6.2/SUR2A genes, which encode cardiac KATP channel subunits, resulted in a cellular phenotype that, in the presence of pinacidil (10 micromol/L), expressed K+ current and gained resistance to hypoxia-reoxygenation (Ca2+ concentration from 99+/-7 to 127+/-11 nmol/L; P>0.05) [11].
• In COS-7 cells transfected with individual channel subunits Kir6.2 or SUR2A, which alone do not form functional cardiac KATP channels, pinacidil did not protect against hypoxia-reoxygenation [11].
• Myocardial oxygen consumption in the rabbit heart after ischemia: hyperpolarized arrest with pinacidil versus depolarized hyperkalemic arrest [12].

Chemical compound and disease context of Pinacidil anhydrous

• BACKGROUND: Our laboratory has demonstrated that the potassium channel openers (PCOs) aprikalim and pinacidil are effective cardioplegic agents but exhibit toxicity at high doses [13].
• Comparative effects of nitroprusside and pinacidil on myocardial blood flow and infarct size in awake dogs with acute myocardial infarction [14].
• Some rats were pretreated with pinacidil (K+(ATP)channel opener), bradykinin, methacholine, or morphine before renal ischemia [15].
• In a double-blind, randomized, crossover study, the effects of intravenous pinacidil, 0.2 mg/kg, were compared with those of hydralazine, 0.3 mg/kg, before and after beta-adrenoceptor blockade in six subjects with hypertension [16].
• The peak rate of rise of left ventricular pressure (dP/dt), the ratio of left ventricular dP/dt and the developed pressure during isovolumic contraction (dP/dt/P), myocardial oxygen consumption, and plasma norepinephrine levels increased after pinacidil administration in the sham-operated dogs, but did not change in the renal hypertension group [17].

Biological context of Pinacidil anhydrous

• At this dose, pinacidil did not alter mean blood pressure before Cs+ and maximal hypertensive response after Cs+ [4].
• At some sites, pinacidil induced an all-or-none repolarization at the end of phase 1 of the action potential, resulting in 55.5 +/- 8.7% abbreviation of APD90 and refractoriness [18].
• Pinacidil increased heart rate, cardiac output, and the peak rate of rise of left ventricular pressure [14].
• METHODS AND RESULTS: Using a blood-perfused parabiotic rabbit heart Langendorff model, myocardial oxygen consumption (MVO2) was compared in hearts protected with either Krebs-Henseleit solution (K-H), pinacidil (50 micromol/L in K-H), or hyperkalemic St [12].
• Because electrical depression attending myocardial ischemia is more accentuated in ventricular epicardium than in endocardium, we endeavored to contrast the effects of pinacidil-induced IK-ATP activation on the electrophysiology of canine ventricular epicardium and endocardium [18].

Anatomical context of Pinacidil anhydrous

• Dogs were randomly assigned to receive intravenous normal saline, nitroprusside, or pinacidil beginning 40 min after the onset of coronary artery occlusion and continuing throughout the occlusion and the first hour of reperfusion [14].
• Furthermore, despite causing a threefold to fourfold increase in normal myocardial blood flow, pinacidil had no effect on either blood flow to ischemic myocardium or infarct size (57 +/- 5%) [14].
• In epicardium, the effects of pinacidil were nonhomogeneous [18].
• In endocardium, pinacidil abbreviated action potential duration (APD90) and refractoriness by 8.0 +/- 2.3% [18].
• Follicular oocytes from Xenopus laevis contain K+ channels activated by members of the recently recognized class of vasorelaxants that include cromakalim and pinacidil and blocked by antidiabetic sulfonylureas, such as glibenclamide [19].

Associations of Pinacidil anhydrous with other chemical compounds

• Because the antihypertensive potassium channel activators pinacidil and cromakalim are known to accelerate repolarization in cardiac tissues, we performed in vitro and in vivo experiments to test the hypothesis that these agents would block the arrhythmogenic effects of delayed repolarization [4].
• Vascular K+ channel openers such as cromakalim, nicorandil, and pinacidil potently stimulate 86Rb+ efflux from slices of substantia nigra [20].
• Sodium nitroprusside caused a membrane potential hyperpolarization and enhanced the response to pinacidil in arteries from diabetic animals [21].
• In the present study, we found that pinacidil potently inhibited Bay K 8644-induced AA vasoconstriction [22].
• The channel was effectively activated by both diazoxide and pinacidil, which is the feature of smooth muscle KATP channels [23].

Gene context of Pinacidil anhydrous

• Cyanoguanidines such as pinacidil and P1075 bind to SUR and enhance MgATP binding to and hydrolysis by SUR, thereby opening K(ATP) channels [24].
• Although pinacidil is a nonselective activator of expressed sK(ATP) channels, diazoxide did not open channels formed by Kir6.1/SUR2A, Kir6.2/SUR2A (known components of cardiac sK(ATP) channels) or Kir6.2/SUR2B [25].
• Incubation of pinacidil with CYP3A4 in the presence of (18)O(2) or H(2)(18)O showed that the amide carbonyl oxygen derived exclusively from molecular oxygen [26].
• SUR2 subtype (A and B)-dependent differential activation of the cloned ATP-sensitive K+ channels by pinacidil and nicorandil [27].
• These results suggest NNC 55-9216 is a SUR1-selective PCO that requires structural determinants, which differ from those needed for activation of the K(ATP) channel by pinacidil and cromakalim [28].

Analytical, diagnostic and therapeutic context of Pinacidil anhydrous

• The MVO2 was significantly (P<.05) elevated in the pinacidil group (0.77+/-0.12) compared with the St Thomas group (0.29+/-0.04) during the first 6 minutes of reperfusion [12].
• Phorbol-12,13-dibutyrate and pinacidil cardioplegia. Novel forms of myoprotection [5].
• Under perforated-patch whole-cell recording conditions, superfusion of atrial myocytes with a 240 mosm/kg solution (control solution, 290 mosm/kg) stimulated whole-cell currents with a magnitude similar to those activated by 10 microM pinacidil [29].
• Heart-lung blocks were flushed and preserved with phosphate-buffered saline (control group) or with one of the solutions containing pinacidil (pinacidil group) or pinacidil + glibenclamide (a KATP blocker) (glibenclamide group) [30].
• Pinacidil is an investigational vasodilator currently undergoing clinical trials as an antihypertensive agent [31].

References