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K D Meisheri

Publications and source records attributed to K D Meisheri.

At least 19 recordsLinked to original sources
PubMed1998

Coronary vasorelaxation by nitroglycerin: involvement of plasmalemmal calcium-activated K+ channels and intracellular Ca++ stores.

This study investigated nitroglygerin (NTG) relaxations in isolated dog coronary artery in comparison with other vascular preparations. Under maximal PNU-46619 precontraction, the coronary artery was significantly more sensitive to NTG than mesenteric artery, mesenteric vein and saphenous vein. In the coronary artery, NTG (1-100 nM) produced relaxations with EC50 = 9.4 nM. In KCl-contracted arteries (20-80 mM KCl), relaxation by NTG was progressively reduced. Relaxation responses to NTG also were inhibited significantly by potent calcium-activated K+ (BK) channel blockers, charybdotoxin (100 nM) and iberiotoxin (200 nM), but not by KATP blockers such as PNU-37883A (10 microM) or PNU-99963 (100 nM). Nitric oxide (0.1-30 nM) and acetylcholine (3-300 nM) also produced relaxations which were significantly attenuated by the BK blockers. In further experiments, NTG (1-100 nM) produced inhibition of PNU-46619-induced SR [Ca++]i release, with an IC50 of 8.5 nM, which was not affected by charybdotoxin. Furthermore, P1075 (50 nM), a KATP opener, did not inhibit agonist-stimulated SR [Ca++]i release. Ryanodine (10 microM), which acts on SR Ca++ release channels, did not alter NTG relaxations, whereas thapsigargin (0.1 microM), a selective inhibitor of SR Ca(++)-ATPase pump, produced pronounced inhibition of NTG relaxations. These results suggest that NTG, in the therapeutic concentration range, produces coronary relaxation primarily via two cellular mechanisms: plasmalemmal BK channel activation and stimulation of SR Ca(++)-ATPase to produce increased SR Ca++ accumulation. These two mechanisms apparently are equally important and act together to produce a unique vasorelaxation profile demonstrated by NTG-type coronary vasodilators.

Animals↗
PubMed1997

Tissue and species variation in the vascular receptor binding of 3H-P1075, a potent KATP opener vasodilator.

A high-affinity receptor site for 3H-P1075 previously observed in rat aorta has been proposed to mediate the vasorelaxation effects of P1075 and other ATP-sensitive K+ channel (KATP) openers. We tested this hypothesis by correlating the receptor binding of 3H-P1075 with its vasorelaxation effects in several isolated vascular preparations from three species: rat, rabbit and dog. In rat aorta and mesenteric artery, 3H-P1075 (1-5 nM) showed high amounts of specific binding (5-10 fmol/mg tissue), which was 48 to 79% of total binding. In contrast, little (< or = 17%) to no specific binding of 3H-P1075 (1-5 nM) was observed in dog coronary artery, dog mesenteric artery or rabbit mesenteric artery. However, all vascular preparations studied relaxed with P1075 (1-100 nM), showing maximal relaxations at 30 to 100 nM. The P1075 relaxation EC50 values in rat aorta, rabbit mesenteric artery and dog coronary artery ranged from 7.5 to 24.1 nM depending on the level of contractile activation. Thus, the pharmacological effect of P1075 could be correlated with the presence of specific receptor binding sites only in rat vascular preparations. These data show that there are significant differences in the characteristics of the proposed specific receptor site for 3H-P1075 in different vascular preparations from different species, and they raise questions regarding the pharmacological significance of this KATP opener binding site. Until such questions are resolved, it appears that the study of functional significance of this receptor site as well as further biochemical characterization of this receptor site may necessitate the use of only the rat vascular preparations.

Animals↗
PubMed1997

Pharmacological characterization of novel cyanoguanidines as vascular KATP channel blockers.

KATP blockers derived from cyanoguanidine KATP opener (P1075) chemistry were characterized in isolated rabbit mesenteric artery and evaluated functionally by their ability to antagonize maximal relaxation induced by pinacidil (1 microM) of norepinephrine (5 microM) contraction. PNU-89692, PNU-97025E and PNU-99963 were identified as KATP blockers with IC50 values of 860, 83 and 18 nM, respectively. Studies with selected chiral compounds demonstrated that the (R)-enantiomers were more potent as KATP blockers than the (S)-enantiomers. Further studies demonstrated that PNU-99963 (1) inhibited relaxations by other KATP openers, such as cromakalim (0.5 microM) and minoxidil sulfate (5 microM); (2) was more potent than the other known vascular KATP blockers (glyburide and PNU-37883A); and (3) acted as a KATP blocker in isolated rat aorta as well as dog coronary artery. PNU-99963 actions were selective because PNU-99963 (100 nM) was without any inhibitory effect on relaxations induced by forskolin (0.5 microM), nitroglycerin (1 microM), D600 (25 or 500 nM) or 15 mM K+-induced relaxations of NE contractions in K+-free PSS. The discovery of KATP blockers and openers from the same chemical series is a first for the K+ channel field. The close structural similarity between P1075 (KATP opener) and PNU-99963 (KATP blocker), stereospecificity of action and potency and selectivity all suggest that these molecules may prove to be valuable tools in understanding the structure and function of the KATP channel complex in vascular smooth muscle.

Adenosine Triphosphate↗
PubMed1996

Cardiovascular effects of the K-ATP channel blocker U-37883A and structurally related morpholinoguanidines.

The cardiovascular effects of the K-ATP channel blocker U-37883A and 5 related morpholinoguanidines were determined in 6 experimental preparations. In anesthetized dogs, U-37883A (0.5-8.0 mg/kg i.v.) increased mean arterial pressure (MAP; +18%) and left ventricular (LV) effective refractory period (ERP; +35%), and decreased LV contractility (-41%). Higher doses of U-37883A (16-32 mg/kg) fatally reduced MAP (-84%), heart rate (HR; -57%) and LV contractility (-72%). In anesthetized rats, U-37883A (1.0-50 mg/kg i.v.) also maximally reduced MAP, HR and LV contractility by 68, 77 and 48%, respectively. U-37883A and its analogs were diuretic in conscious rats (1.5-15 mg/kg i.v.) and blocked pinacidil in rabbit mesenteric artery (EC50 = 0.5-50 microM). In rabbit papillary muscle, 50 microM U-37883A significantly reduced force of contraction (-33%) and prolonged conduction time (+244%). Milder papillary effects were seen with the N'-OH analog U-45194A, which did not depress LV contractility in intact rats. In conscious dogs, oral U-45194A (50 mg/kg) was diuretic but reduced LV stroke volume and increased peripheral vascular resistance. These studies characterize U-37883A's systemic cardiovascular and direct myocardial effects, and identify U-45194A as a less cardiac depressant analog having U-37883A-like diuretic and functional K-ATP channel blocking activities.

Adamantane↗
PubMed1994

Comparative effects of the potassium channel openers cromakalim and pinacidil and the cromakalim analog U-89232 on isolated vascular and cardiac tissue.

ATP-sensitive potassium (K+ATP) channel openers such as cromakalim and pinacidil exhibit both potent vasodilatory and anti-ischemic properties. U-89232, a cyanoguanidine analog of cromakalim, has recently been found to exhibit myocardial protection during ischemia without altering in vivo hemodynamics. We examined the effects of U-89232, cromakalim and pinacidil in isolated vascular and cardiac tissue and tested whether glyburide, a KATP channel blocker, could antagonize their effects. All three compounds produced concentration-dependent relaxation in isolated vascular segments, with cromakalim being approximately 100-fold more potent than either pinacidil or U-89232. Glyburide completely antagonized the effects of pinacidil but merely blunted the effects of cromakalim and U-89232. In an isolated rabbit cardiac tissue preparation, U-89232 had little effect on maximum tension in cardiac muscle, whereas cromakalim and pinacidil significantly decreased maximum developed tension in a concentration-dependent manner. Glyburide effectively antagonized the effects of cromakalim and pinacidil in cardiac tissue. These data suggest that U-89232, although chemically related to cromakalim, possesses activity which is not common to known potassium channel openers.

Animals↗
PubMed1993

Role of calcium-activated K+ channels in vasodilation induced by nitroglycerine, acetylcholine and nitric oxide.

A comparative analysis was carried out of the sensitivities of in vitro vasorelaxations by nitroglycerine (NTG), acetylcholine (ACh) and nitric oxide (NO) to blockade by glyburide, a blocker of ATP-sensitive K+ channels (KATP), as well as to blockade by charybdotoxin (ChTX) and iberiotoxin (lbTX), potent blockers of calcium-activated K+ channels (KCa). In the isolated rabbit mesenteric artery (RMA) precontracted with 5 microM norepinephrine (NE), ACh (0.01-1 microM), NTG (0.01-5 microM) and NO (0.075-2.7 microM) produced a dose-dependent vasodilation. Glyburide (0.5 microM) had no significant effect on relaxation dose-response curves (DRCs) to ACh, NTG or NO. In contrast, glyburide completely abolished the relaxation DRC by pinacidil, a known KATP opener. ChTX (10 or 100 nM) caused an inhibition of relaxation DRCs to ACh, NTG and NO. In all cases, ChTX shifted the relaxation DRC to the right and depressed the maximal response. Another potent KCa blocker, lbTX (20 nM) also significantly inhibited relaxation DRCs to NTG, ACh and NO and inhibited maximal relaxation response to SNP. The effects of ChTX and lbTX were selective; they did not inhibit relaxations by pinacidil and forskolin. Finally, it was observed that the use of 80 mM K+ as a contractile stimulus inhibited NTG relaxations in a manner similar to the KCa blockers. Collectively, these data provide strong support for the hypothesis that the activation of KCa plays an important role in mediating the vasorelaxation caused by NTG, SNP, ACh and NO.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1993

Synergistic effects of glyburide and U-37883A, two structurally different vascular ATP-sensitive potassium channel antagonists.

Glyburide, a sulfonylurea, and U-37883A, a guanidine (4-Morpholinecarboximidine-N-1-Adamantyl-N' cyclohexylhydrochloride), have been previously characterized as antagonists of the vascular ATP-sensitive K+ channels (KATP). In this report, the in vitro interaction between these two chemically distinct KATP antagonists was investigated using isolated rabbit mesenteric artery. The KATP antagonism was functionally studied as the inhibition of vasodilation produced by various KATP openers as follows: pinacidil (1 microM), minoxidil sulfate (5 microM), cromakalim (0.5 microM) and RP-49356 (1 microM). Glyburide alone produced inhibition in the concentration range of 50 to 500 nM with the glyburide IC50 ranging from 72 to 148 nM. U-37883A alone produced inhibition in the concentration range of 0.5 to 5 microM, with the U-37883A IC50 ranging from 0.78 to 1.4 microM. In the presence of a threshold U-37883A concentration of 0.5 microM, the glyburide inhibition dose-response curve against pinacidil was significantly shifted to the left and the glyburide IC50 was lowered from 72 to 3.9 nM, representing an 18-fold decrease. Similarly, in the presence of a threshold glyburide concentration of 50 nM, the U-37883A inhibition dose-response curve against pinacidil was significantly shifted to the left and the U-37883A IC50 was lowered from 780 to 96 nM, representing an eightfold decrease. Thus, glyburide and U-37883A potentiated each other's effects as KATP blockers. This synergistic interaction between glyburide and U-37883A was observed independently of the pinacidil, cromakalim or minoxidil sulfate used to produce vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adamantane↗
PubMed1993

4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydrochloride (U-37883A): pharmacological characterization of a novel antagonist of vascular ATP-sensitive K+ channel openers.

This study describes the in vitro and in vivo characteristics of a guanidine 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl-hydroc hloride (U-37883A), as an antagonist of vascular ATP-sensitive K+ channels (KATP). In isolated rabbit mesenteric artery, the antagonistic effects of U-37883A (0.5-5 microM) were studied against vasorelaxation produced by cromakalim (0.5 microM), minoxidil sulfate (5 microM), pinacidil (1 microM) and RP-49356 (1 microM). The dose-response curves for U-37883A against all four potassium channel openers were similar with U-37883A, IC50S ranging from 0.78 to 1.4 microM, suggesting that U-37883A is producing inhibition by acting at a step that is common to all four potassium channel openers during their activation of the vascular KATP. In contrast, U-37883A at 10 microM did not inhibit relaxation dose-response curves by nitroglycerine, forskolin or D600. U-37883A (1 or 10 microM) effectively inhibited as well as reversed 42K efflux-stimulated by cromakalim (1 microM) or minoxidil sulfate (5 microM). Finally, U-37883A (3 mg/kg i.v.) was found to inhibit significantly as well as reverse hypotension produced by minoxidil (1 mg/kg i.v. or 3 mg/kg p.o.), cromakalim (0.5 mg/kg p.o.) and pinacidil (0.3 mg/kg i.v.) in rats, cats and dogs. In contrast, the in vivo responses to phenylephrine, nitroglycerine, sodium nitroprusside or isoproterenol were not altered. U-37883A thus appears to be the first nonsulfonylurea shown to block consistently and selectively the in vitro as well as the in vivo pharmacological responses to various potassium channel openers. This structurally novel KATP antagonist therefore would be useful for further characterizing the mechanisms of pharmacological modulation of the KATP in a variety of cell systems.

Adamantane↗
PubMed1991

Nicorandil-induced vasorelaxation: functional evidence for K+ channel-dependent and cyclic GMP-dependent components in a single vascular preparation.

Using a series of functional criteria, we wished to evaluate the K+ conductance mechanism and the cyclic GMP mechanism implicated in the actions of nicorandil (NIC) as a vasodilator. In rabbit isolated superior mesenteric artery, NIC exhibited two relaxation dose-response curves (DRCs): one with a lower IC50 of 4.8 x 10(-6) M for norepinephrine (NE 5 microM) contraction, and another with a higher IC50 of 1.4 x 10(-4) M for 80 mM K+ contraction. K+ channel blockers (TEA 1-10 mM), Ba2+ (0.1-0.5 mM), glyburide (1 microM), and increased [K+]ex (20 mM), all caused significant attenuations in the ability of NIC to relax NE contraction, but did not influence the ability of NIC to relax high-K+ contraction. Pretreatment with 5 microM methylene blue, a guanylate cyclase inhibitor, produced a pronounced inhibition of nitroglycerine (NTG) relaxation, but only a marginal inhibitory effect on the NIC relaxation DRC for NE contraction. Functional studies demonstrated that the inhibitory effect of NIC on NE-sensitive intracellular Ca2+ release occurred in the same concentration range as that required for relaxation of 80 mM K+ contractions (10(-5)-10(-3) M). Furthermore, NIC also caused increases in cellular cyclic GMP levels at this higher concentration range. Finally, NIC relaxation of NE contraction was not prone either to self-tolerance (30 mM NIC preexposure) or cross-tolerance (0.55 mM NTG preexposure) development. In contrast, a modest but significant degree of self-tolerance to NIC could be demonstrated under high-K+ contraction condition. These studies thus show the existence of both cellular mechanisms for NIC in the same vascular preparation and further show that these two mechanistic components are separate and independent. The K+ channel-dependent component occurs at lower concentrations, is blocked by K+ channel blockers, is not inhibited by methylene blue, is not associated with increases in cyclic GMP, and is not prone to tolerance development. In this, NIC resembles other K+ channel openers. The cyclic GMP-dependent component is evident at relatively higher concentrations, is associated with inhibition of [Ca2+]i release, is associated with increases in cyclic GMP levels, and is prone to tolerance development. In this, NIC resembles other nitrovasodilators. A combination of these characteristics of the actions of NIC may contribute to the differences in the acute versus chronic hemodynamic profile of NIC.

Animals↗
PubMed1991

Role of protein sulfation in vasodilation induced by minoxidil sulfate, a K+ channel opener.

Evidence from contractile, radioisotope ion flux and electrophysiological studies suggest that minoxidil sulfate (MNXS) acts as a K+ channel opener in vascular smooth muscle. This study was designed to examine possible biochemical mechanisms by which MNXS exerts such an effect. Experiments performed in the isolated rabbit mesenteric artery (RMA) showed that MNXS, 5 microM, but not the parent compound minoxidil, was a potent vasodilator. Whereas the relaxant effects of an another K+ channel opener vasodilator, BRL-34915 (cromakalim), were removed by washing with physiological saline solution, the effects of MNXS persisted after repeated washout attempts. Furthermore, after an initial exposure of segments of intact RMA to [35S] MNXS, greater than 30% of the radiolabel was retained 2 hr after removal of the drug. In contrast, retention of radiolabel was not detected with either [3H]MNXS (label on the piperidine ring of MNXS) or [3H]minoxidil (each less than 3% after a 2-hr washout). These data suggested that the sulfate moiety from MNXS was closely associated with the vascular tissue. To determine if proteins were the acceptors of sulfate from MNXS, intact RMAs were incubated with [35S]MNXS, and then 35S-labeled proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and analyzed by fluorography. Preferential labeling of a 116 kD protein was detected by 2 and 5 min of treatment. A 43 kD protein (resembling actin) also showed significant labeling. A similar profile of 35S-labeled proteins was observed in [35S] MNXS-treated A7r5 rat aortic smooth muscle cells, suggesting that the majority of proteins labeled by [35S]MNXS in intact RMA were components of smooth muscle cells. (ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Characterization of K+ channel-dependent as well as -independent components of pinacidil-induced vasodilation.

The mechanisms of pinacidil-induced direct vasodilation were studied in vitro in RMA and RAO. In RMA, pinacidil produced dose-dependent relaxations of norepinephrine (5 microM)-induced contractions with an IC50 of 0.2 microM. This component of pinacidil relaxation appeared to be dependent on K+ conductance because pretreatment with tetraethylammonium (10 mM), Ba++ (0.5 mM), glyburide (1 microM) and 20 mM K+ all caused a rightward shift of the pinacidil dose-response curve (DRC) and a corresponding increase in the pinacidil IC50. However, additional relaxation effects of pinacidil were still evident in the presence of various K+ channel blockers. Pinacidil also showed a relaxation DRC under the condition of 80 mM K+ contraction in both RMA and RAO with IC50 values of 27 and 50 microM, respectively. Pinacidil could also produce maximal relaxation in RMA and RAO remained unaffected in 145 mM K+ (zero Na+) depolarizing solution suggesting a lack of dependence on Na(+)-Ca++ exchange mechanism for this action of pinacidil. Studies using 1 or 3 min pulse labeling with 45Ca showed an absence of an inhibitory effect of pinacidil (at 50 and 100 microM) on unidirectional 45Ca influx stimulated by high-K+. Net 45Ca uptake studies showed that pinacidil inhibited high-K+ stimulated 45Ca uptake at 100 but not at 50 microM. Ryanodine (10-100 microM) was used as a tool to investigate the role of sarcoplasmic reticulum (SR) in this action of pinacidil. Under the condition in which ryanodine (10-100 microM) treatment was found to cause the SR to be nonfunctional, pinacidil relaxation DRC remained unaltered, suggesting a lack of a stimulatory effect of pinacidil on SR Ca++ accumulation. These data thus show that the K+ channel-independent effect of pinacidil does not involve to any significant degree an effect of pinacidil on plasmalemmal voltage-sensitive Ca++ channels, SR Ca++ stores, Na(+)-Ca++ exchange or membrane hyperpolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

A sensitive in vitro functional assay to detect K(+)-channel-dependent vasodilators.

This study describes a sensitive in vitro relaxation assay using isolated rabbit mesenteric artery to detect the activity of a vasodilator as a K(+)-channel activator. Thus, comparison of several known K(+)-channel activators was made with other vasodilators known to work via various cellular mechanisms. The vasodilators used were minoxidil sulfate (MNXS; 5 microM), BRL-34915 (cromakalim, 0.1 microM), nicorandil (10 microM), pinacidil (1 microM), diazoxide (100 microM), sodium nitroprusside (10 microM), forskolin (1 microM), D600 (0.5 and 10 microM), hydralazine (10 microM), and viprostal (PGE1 analog, 5 microM). The concentrations chosen were equipotent to produce greater than 80% relaxation of the maximal norepinephrine (NE) (5 microM) contraction. At these concentrations, MNXS, cromakalim, pinacidil, nicorandil, and diazoxide were found to be ineffective in producing relaxation of 80 mM K(+)-contractions. Subsequently, pretreatment of tissues with 20 mM K+ before NE contraction was found to attenuate relaxation significantly by these agents, but had not effect on the relaxations by forskolin or D600. These initial criteria helped to establish cromakalim, pinacidil, nicorandil, and diazoxide as compounds acting similarly to MNXS as K(+)-channel-dependent. In another set of experiments, the effects of tetraethylammonium (TEA) (10 mM), Ba2+ (0.5 mM), and glyburide (1 microM) as K(+)-channel blockers were examined. Again it was found that these blockers had the most inhibitory effect on the class of compounds identified as K(+)-channel activators. Additionally, it was found that these K(+)-channel activators were without any significant effect on the NE-sensitive intracellular Ca2+ release as studied by contraction in a Ca2(+)-free solution. Thus, this series of functional criteria clearly show that the profile of these K(+)-channel activators is distinctly different from the vasodilators working via other mechanisms such as cyclic AMP (cAMP) (forskolin), cyclic GMP (cGMP) (nitroprusside), and Ca2+ antagonists (D600). It is suggested that appropriately defined, systematic functional studies, such as the one described here, can provide a sensitive and reproducible vascular model to discover and delineate the role of pharmacologically relevant mechanisms for vasodilation.

Animals↗
PubMed1990

Generation of vasoactive substances in trout and rat plasma by trypsin and kallikrein.

In the preceding study we demonstrated kallikrein-like enzymatic activity in trout tissues and showed that kallikrein incubated with trout plasma (T60K) produces a vasopressor substance(s). The present study further examines the effects of T60K in fish and mammals in vitro and in vivo. T60K produced a dose-dependent pressor response in both trout and rats, whereas kallikrein-activated rat plasma (R60K) was pressor in trout and depressor in rats. Captopril did not affect the response of rats to T60K or R60K. Phenoxybenzamine attenuated the T60K response in trout but not in rats, thus T60K effects in trout are partially mediated through catecholamines. Blockade of angiotensin II (ANG II) receptors in rats with [Sar1,Ala8]-ANG II abolished the pressor effects of T60K. T60K produced dose-dependent contractions in isolated trout and rabbit arteries; ANG II was ineffective in trout arteries. T60K-contracted trout arteries were relaxed by atrial natriuretic peptide and forskolin, whereas diltiazem and sodium nitroprusside were without effect. [Sar1,Ala8]ANG II inhibited T60K-induced contractions of rabbit arteries and relaxed rings previously contracted with T60K. The active component of T60K has a molecular weight less than 10,000, is heat stable, and is inactivated by peptidases. It is immunologically different than mammalian angiotensins but binds to and displaces radiolabeled ANG II from ANG II receptors. These results suggest that kallikrein forms a vasoactive substance(s) in trout plasma that is neither bradykinin nor ANG II but is similar to the latter in its pharmacological effects.

Animals↗
PubMed1990

Factors affecting rabbit mesenteric artery smooth muscle sensitivity to calcium antagonists.

The sensitivity of rabbit isolated superior mesenteric artery to Ca++ antagonists was examined under various conditions. Relaxation dose-response curves for D600 or nifedipine were generated, and IC50 values were calculated. In the first series of experiments, D600 or nifedipine IC50 was found to be 20-25-fold greater for norepinephrine (NE, 5 microM) contraction than for 80 nM K+ contraction. Even when the tissues were depolarized with 80 mM K+ before NE contraction, D600 or nifedipine IC50 still remained significantly greater compared with 80 mM K+ alone and remained closer to that during NE alone. Also a protocol was designed to study NE-induced phasic contraction in EGTA-physiological salt solution (a functional indicator of intracellular Ca++ release) as well as NE-induced sustained contraction after readdition of Ca++. The effects of varying [K+]ex (0-80 nM range) on NE-induced [Ca++]i release as well as on the D600 IC50 for NE contraction was studied. Increasing [K+]ex was found to enhance NE-sensitive [Ca++]i release and lower the D600 IC50 for NE contraction. Thus, conditions causing an increase in the ability of NE to cause [Ca++]i release were associated with an increase in the sensitivity of NE contraction to D600. These data provide functional evidence that the receptor-agonist sensitive Ca++ influx process in vascular smooth muscle is not solely regulated by changes in membrane potential. Additional mechanisms, such as a modulatory role of [Ca++]i release, in this process are implicated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Effects of atrial natriuretic factor on isolated arteries and perfused organs of trout.

Atrial natriuretic factor (ANF) increases blood pressure when injected into conscious trout [Duff and Olson, Am. J. Physiol. 251 (Regulatory Integrative Comp. Physiol. 20): R639-R642, 1986]. The effects and mechanisms of action of ANF on trout vessels in vitro were examined in the present study using isolated celiacomesenteric arterial rings, perfused gill arches, and a two-artery perfused trunk preparation. In all experiments, ANF alone either relaxed trout vessels or had no effect. ANF inhibited contractions of arterial rings produced by a variety of agonists in part through inhibition of intracellular calcium release. In perfused gills, ANF attenuated epinephrine (EPI) alpha-mediated vasoconstriction but had no effect on beta-stimulated increases in water permeability. ANF only slightly lowered an EPI-induced increase in resistance in either pathway of the perfused trunk. These results indicate that the vascular effects and mechanism of action of ANF are similar in fish and mammals and that the pressor response to ANF injection in vivo is mediated through central or secondary effects.

Animals↗
PubMed1988

Mechanism of action of minoxidil sulfate-induced vasodilation: a role for increased K+ permeability.

The mechanism of smooth muscle relaxing effect of minoxidil sulfate (MxSO4) was investigated in isolated rabbit superior mesenteric artery. MxSO4 (5 X 10(-6) M) was found to effectively relax maximal norepinephrine (NE; at 5 X 10(-6) M) contraction, but failed to relax 80 mM K+-induced contraction. MxSO4-induced relaxation was endothelium independent. When the tissues were exposed to increased extracellular K+ (10-25 mM), and then contracted with NE, the relaxation response to MxSO4 was significantly attenuated. Tetraethylammonium (5-10 mM) pretreatment caused pronounced inhibition of MxSO4-induced relaxation. Pretreatment with ouabain (0.5-5 microM) also significantly inhibited MxSO4 relaxation. This effect of ouabain was found to be due to its effect on K+ gradient. These data suggested a role of K+ permeability during MxSO4 relaxation which was further confirmed when it was found that MxSO4 can cause a significant stimulation of 42K efflux from the mesenteric artery preloaded with 42K. It is suggested that MxSO4 may act as a K+ channel agonist to affect the plasmalemmal Ca++ permeability during agonist activation. Consistent with this, MxSO4 was demonstrated to cause an inhibition of NE-stimulated 45Ca influx in this tissue. Such a strong dependence on K+ permeability makes MxSO4 a unique vasodilator among the clinically used vasodilators.

Animals↗
PubMed1987

Biochemical mechanisms by which minoxidil sulfate influences mammalian cells.

The antihypertensive effect of minoxidil has been shown to occur via direct vasodilation induced by its active metabolite, minoxidil sulfate (MxSO4). Thus, an in vitro vascular smooth muscle preparation was used as a model to investigate cellular biochemical mechanisms influenced by MxSO4. In rabbit isolated superior mesenteric artery, the contractions produced by receptor agonists such as norepinephrine (NE) were relaxed by about 85% with MxSO4. In contrast, MxSO4 was without any effect on 80 mM KCl-induced contraction. Furthermore, pretreatment of the tissues with tetraethlammonium (TEA, a K+ channel blocker), or ouabain, or 10-25 mM KCl, all caused pronounced inhibition of MxSO4-induced relaxation of NE-induced contraction. These investigations revealed that MxSO4-induced relaxation could be effectively inhibited by treatments that interfere with plasmalemmal K+ permeability. It is proposed that MxSO4 acts like a K+ channel agonist to enhance K+ permeability; this should result in hyperpolarization and cause reduction in agonist-stimulated Ca2+ influx. The end result is a decrease in cytoplasmic free Ca2+ concentration, and thus relaxation. Consistent with this, we could also demonstrate enhancement of 42K efflux as well as inhibition of NE-stimulated 45Ca influx. The above-proposed mechanism appears specific for MxSO4 since it was not shared by forskolin (a cyclic-AMP-increasing agent), sodium nitroprusside (a cyclic-GMP-increasing agent) or D600 (a Ca2+ antagonist). The relevance of the proposed unique cellular mechanism (i.e. K+ permeability) of MxSO4 to its hair growth effect remains to be examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗