Biomedical subjects

K Hermsmeyer

Publications and source records attributed to K Hermsmeyer.

At least 19 recordsLinked to original sources

PubMed2001

Progesterone regulation of vascular thromboxane A(2) receptors in rhesus monkeys.

We hypothesized that progesterone regulates thromboxane A(2) receptor (TxA(2)R) density in primate vascular muscle and that TxA(2)R density correlates with coronary reactivity in vivo and in vitro. Reactivity to serotonin + U-46619 was determined by angiography in surgically postmenopausal [ovariectomized (Ovx)] rhesus monkeys without progesterone replacement and after 2-wk progesterone treatment (1-2 ng/ml). In untreated Ovx animals, 100 micromol/l serotonin + 1 micromol/l U-46619 (syringe concentrations) provoked vasospasm-like constrictions in six of six monkeys; zero of six progesterone-treated monkeys developed vasospasms. Sustained Ca(2+) responses in vascular muscle cells isolated from Ovx coronaries (208 +/- 63% of basal 20 min after stimulation) treated with serotonin + U-46619 contrasted with transient Ca(2+) responses (143 +/- 18% of basal and decreasing 5 min after stimulation) in progesterone-treated monkeys. The maximum density of [1S-(1I,2J(5Z),3I(1E,3R*),4I)]-7-[3-(3-hydroxy-4-(4'-[(125)I]iodophenoxy)- 1-butenyl)-7-oxabicyclo[2.2.1]heptan-2-yl]-5-heptenoic acid ([(125)I]-BOP) binding was greater (P < 0.01) in carotid arteries and aortic membranes from Ovx (109 +/- 11 fmol/mg) compared with progesterone-treated (43 +/- 15 fmol/mg) monkeys. TxA(2)R immunolabeling revealed greater coronary TxA(2)R labeling in Ovx compared with progesterone-treated monkeys. The results suggest that progesterone can decrease arterial TxA(2)R in Ovx monkeys.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1999

Percutaneous absorption of progesterone in postmenopausal women treated with transdermal estrogen.

OBJECTIVE: The objective of this study was to evaluate the serum levels of progesterone resulting from the application of a progesterone cream to the skin. STUDY DESIGN: Six postmenopausal women were evaluated at a university clinic over a 4-week period. RESULTS: Transdermal estradiol 0.05 mg was applied 2 days before the first application of progesterone (30 mg/d) and was continued throughout the study. Patches were changed twice a week. Progesterone cream was applied once a day for 2 weeks. On day 15 and for the next 2 weeks, the progesterone cream was applied twice daily (60 mg/d). Serum 17beta-estradiol and progesterone were measured at 9 different times over a 24-hour period on day 1 and at weekly intervals for the 4-week duration of the study. Serum 17beta-estradiol concentrations varied among women, with mean concentrations of 40 to 64 pg/mL observed. Consistency in 17beta-estradiol concentrations was found within individual persons throughout the study. Serum progesterone concentrations also varied among women, with mean concentrations ranging from 1.6 to 3.3 ng/mL. After 2 weeks of percutaneous dosing, progesterone concentrations were sustained for at least 8 hours and were consistent within a given person. An appropriate increase in progesterone concentration occurred after 4 weeks compared with 2 weeks of application. Individually, a 0.53 correlation, significant at P <.0001, was seen between the absorption of 17beta-estradiol and progesterone. CONCLUSION: Significant increases in serum concentrations of progesterone were observed in all of the women studied. The percutaneous absorption of progesterone correlates strongly with the absorption of transdermal 17beta-estradiol. There is variance in absorption of progesterone just as with 17beta-estradiol, and the 2 measures are closely correlated. The percutaneous application of progesterone cream appears to be a safe and effective route of administration.

Administration, Cutaneous↗

PubMed1998

In vitro modulation of primate coronary vascular muscle cell reactivity by ovarian steroid hormones.

Susceptibility to drug-induced coronary vasospasm in rhesus monkeys increases after removal of the ovaries and can be normalized by adding back physiological levels of estradiol-17ss (E2) and/or natural progesterone (P) in vivo as reported recently by our group. Furthermore, the reactivity status (Ca2+ and protein kinase C responses) of freshly isolated and primary culture coronary artery vascular muscle cells (VMC) mimic the intact coronary artery responses to 5-HT + U46619. Since coronary reactivity is maintained in the isolated VMC, we hypothesized that the reactivity state inherent in the VMC was modulated directly by ovarian steroids in vitro as in the whole animal. To test this hypothesis, we treated hyperreactive VMC from ovariectomized (ovx) monkeys in vitro with E2 or P and measured VMC reactivity to combined stimulation with 5-HT and U46619, as determined by the amplitude and especially the duration of intracellular Ca2+ signals, as well as protein kinase C (PKC) activation/translocation. VMC were treated for 12 96 h with 3 100 pg/ml E2 (10 365 pM) and/or 0.3 3 ng/ml P (0.95 9.5 nM). Hyperreactive responses to the combination of 5-HT and U46619 in untreated VMC were significantly and dose-dependently reduced by treatment in vitro with physiological levels of either E2 or P for at least 24 h. Both the early transient and late sustained increases in intracellular Ca2+ and PKC translocation were blunted, and the effects of 0.2 nM E2 and 3.2 nM P were specifically antagonized by the receptor blockers ICI 182,780 (200 nM) and RU486 (15 nM), respectively. Antibodies to the estrogen receptor and progesterone receptor labeled nuclei in VMC, which were also positively labeled by a smooth muscle myosin heavy chain monoclonal antibody. These data indicate that natural ovarian steroids directly reduce hyperreactive 5-HT and thromboxane A2-stimulated Ca2+ and PKC responses of coronary artery VMC from surgically menopausal rhesus macaques. We hypothesize that vascular hyperreactivity, which may be a critical factor involved in the increased incidence of coronary artery vasospasm and ischemic heart disease in postmenopausal women, can be normalized by E2 and/or P through direct actions on coronary artery vascular muscle cells.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1998

Role of T channels in cardiovascular function.

Although two types of Ca2+ channels are found to occur in the cardiovascular system, very little is known about one of them, primarily because a pharmacological blocking agent has been lacking. The enigmatic transient (T)-type Ca2+ channel has finally been recognized by a selective Ca2+ antagonist. The novel tetralol Ca2+ antagonist, mibefradil, is a selective T-type Ca2+ channel blocker that produces effective vasodilatation with additional inhibitory actions on blood vessel wall and left ventricular thickening. The availability of a blocking agent has begun to reveal the significance of T-type Ca2+ channel signals. Selective T-type Ca2+ channel blockade characteristics include vascular selectivity, freedom from negative cardiac inotropism, consistent and predictable reduction in heart rate, reduction in subendothelial proliferation, and increased survival of severely hypertensive and heart failure animal models. Mibefradil increases coronary blood flow without increasing myocardial oxygen consumption, and by decreasing heart rate and thus time spent in diastole, improves subendocardial perfusion. Improved perfusion of the myocardial wall and lowered heart rate appear to normalize the underlying pathophysiological factors, improve heart failure, and provide long-term protection. Thus, T-type Ca2+ channel blockade offers significant new cardiovascular protective benefits, even in the presence of critical pathophysiological elements (i.e. increased heart rate and neurohumors in the presence of decreased ejection fraction and contractility) found in heart failure.

Animals↗

PubMed1998

Ovarian steroid protection against coronary artery hyperreactivity in rhesus monkeys.

Our hypothesis was that estrogen and progesterone modulate coronary artery reactivity in rhesus monkeys. Adult ovariectomized (ovx) monkeys were treated for 1, 2, or 4 wk with physiological concentrations of 17 beta-estradiol (E2), natural progesterone (P), and/or therapeutic levels of medroxyprogesterone acetate (MPA). Steroid concentrations in venous blood, coronary artery estrogen receptor (ER) and progesterone receptor (PR) localization, and isolated vascular muscle cell (VMC) Ca2+ and protein kinase C responses to serotonin and U46619 (a thromboxane A2 mimetic) were measured. Ovx monkey VMC responses were hyperreactive, showing prolonged increases in intracellular Ca2+ and protein kinase C that correlated with exaggerated in vivo coronary artery vasoconstrictor responses. The hyperreactive Ca2+ responses were abolished by in vivo treatment with E2 and/or P. However, VMC from ovx monkeys treated with the combination of E2 and MPA or E2, P, and MPA remained hyperreactive to vasoconstrictor stimuli, suggesting that MPA negated the protective effects of E2. ER were detected primarily in interstitial and endothelial cells and a minor fraction of the VMC. PR were localized to coronary artery VMC and interstitial cell nuclei. In vivo treatment of ovx monkeys with E2 tended to up-regulate PR in VMC, but MPA appeared to down-regulate PR expression. These results suggest that E2 and P replacement decreases coronary artery reactivity through direct interactions with ER and PR in coronary artery VMC.

Animals↗

PubMed1997

Reactivity-based coronary vasospasm independent of atherosclerosis in rhesus monkeys.

OBJECTIVES: We studied the hypothesis that in the absence of vascular pathology, coronary artery vasospasm occurs as a result of local regions of vascular muscle hyperreactivity. We aimed to explore the basis for a functional etiology of those vasospasms not explained on a structural basis. BACKGROUND: Ovariectomized rhesus monkeys (Macaca mulatta) without injury or significant vascular disease were stimulated with platelet release products, and angiograms were compared with those from vasospasms induced in human patients. METHODS: We used intracoronary (IC) injections of serotonin, thromboxane A2 (U46619), endothelin 1 or angiotensin II in concentrations 3 to 10 times that which reduced coronary artery diameter by 50%. RESULTS: Although no agent alone caused vasospasm, the combination of pathophysiologic concentrations of serotonin and the stable thromboxane A2 mimetic, U46619, injected through an IC catheter, synergistically caused coronary vasospasm on the second or third challenge in five of seven monkeys. These drug-induced vasospasms were similar to vasospasms induced by mechanical injury followed by serotonin, and to those stimulated in human IC diagnostic tests, as judged by onset, appearance, kinetics and vasodilator reversal. CONCLUSIONS: These studies in ovariectomized monkeys revealed that coronary vasospasm can be stimulated without preexisting vascular pathology, endothelial denudation or injury. Reproducible vasospasm of primate coronary arteries in response to these two endogenous pathophysiologic vasoconstrictors, which are thought to be precipitating stimuli in the etiology of vasospasm, suggests that structure-independent epicardial vasospasm can be an important element in serious cardiac ischemic events, particularly the focal, persistent vasospasms that occur without plaques or injury.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1997

Physiologic and pathophysiologic relevance of T-type calcium-ion channels: potential indications for T-type calcium antagonists.

The family of voltage-gated calcium-ion (Ca2+) channels is critical in the role of transmembrane signaling of excitable cells throughout the body. Within the cardiovascular system, two types of Ca2+ channels have been identified: the L-type channel and the T-type channel. These two types of Ca2+ channels have distinct electrophysiologic identities, and although the roles of the T-type Ca2+ channels have not been firmly established, there are many reasons for believing that the roles of the T-type and L-type Ca2+ channels are distinct. T-type Ca2+ channels have the appropriate characteristics to generate pacemaker activity in the sinoatrial node. In vascular smooth muscle, they appear to be involved in maintenance of coronary and peripheral vasomotor tone and control of vascular growth and remodeling. Characterization of the T-type Ca2+ channels will be facilitated by the availability of mibefradil, a novel calcium antagonist that selectively blocks T-type Ca2+ channels. Mibefradil is associated with a reduction in heart rate but not with negative inotropic effects or neurohormonal stimulation. It is thought that the unique pharmacologic effects of mibefradil are related to blockade of T-type Ca2+ channels, and it is hypothesized that this action will have a positive impact on cardiovascular morbidity and mortality via cardioprotective and renoprotective effects. However, much work needs to be done to fully test this hypothesis.

Angina Pectoris↗

PubMed1997

Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm.

Cardiovascular disease, the major cause of death in post-menopausal women, can be reduced by replacement of ovarian steroid hormones. To compare medroxyprogesterone with progesterone as the progestin in hormone replacement therapy from the standpoint of coronary artery vasospasm, we treated ovariectomized rhesus monkeys with physiological levels of estradiol-17 beta in combination with medroxyprogesterone or progesterone for four weeks. Coronary vasospasm in response to pathophysiological stimulation without injury showed that progesterone plus estradiol protected but medroxyprogesterone plus estradiol failed to protect, allowing vasospasm. We conclude that medroxyprogesterone in contrast to progesterone increases the risk of coronary vasospasm.

Animals↗

PubMed1997

Ca2+ release mechanism of primate drug-induced coronary vasospasm.

Cellular mechanisms of protection against drug-stimulated coronary vasospasm were studied by multiweek estrogen plus progesterone (P) vs. medroxy-progesterone acetate (MPA) treatments by measuring intracellular Ca2+ and protein kinase C (PKC) signals. Ovariectomized monkeys (OVX) were treated by slow-release implants with either P or MPA for 4 wk added to estradiol-17 beta (E2) begun 2 wk earlier. A third group received E2 for 2 wk and withdrawal of E2 (W; no steroid treatment) during the last 4 wk. OVX coronary artery vascular muscle cells (VMC) in primary culture conditions were labeled by the fluorescent indicators, fluo 3 and hypericin, respectively, to study intracellular Ca2+ and PKC mechanisms of coronary artery hyperre-activity, using digital analysis of single VMC by photon-counting camera. Stimulation by 10 microM serotonin and 100 nM U-46619 (thromboxane A2 mimetic) caused Ca2+ increases (2-5 min) and no PKC activation in VMC from five P-treated monkeys but prolonged (> or = 30 min) increases in both Ca2+ and PKC signals in VMC from six MPA-treated monkeys or seven W-treated monkeys; these P vs. MPA (or W) differences were maintained > or = 14 days. We hypothesize that hyperreactivity in VMC from MPA- or W-treated monkeys results from accelerated prolonged Ca2+ release, with concomitant PKC activation, and that MPA (but not P) negates the coronary vasospasm protective effect of E2.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1995

Effects of mibefradil on intracellular Ca2+ release in cultured rat cardiac fibroblasts and human platelets.

The Ca2+ antagonist mibefradil at supratherapeutic concentrations induced a sustained increase of cytosolic Ca2+ in cultured rat cardiac fibroblasts and human platelets which lack sensitivity to K+ depolarization and Ca2+ channel block by verapamil or other Ca2+ antagonists. At concentrations above 10 microM, mibefradil elevated substantially cytosolic [Ca2+] without affecting the peak level of agonist-induced Ca2+ transients. These Ca2+-mobilizing actions of 10 or 100 microM mibefradil stand in contrast to the Ca2+ antagonism and relaxation of vascular muscle at 1 microM concentrations. Since a substantial part of mibefradil-induced increase in cytosolic Ca2+ was independent of extracellular Ca2+, and in order to define better the mechanism of Ca2+ increase, we exposed permeabilized cultured rat cardiac fibroblasts and human platelets to mibefradil at concentrations sufficiently high to identify covert effects. In permeabilized fibroblasts or platelets mibefradil at concentrations above 10 microM activated dose-dependent Ca2+ release from intracellular Ca2+ stores. Verapamil had no effect at concentrations of up to 100 microM. Mibefradil-induced Ca2+ release was not affected by ryanodine, thapsigargin, removal of ATP or dithioerythreitol, indicating that neither Ca2+ - nor disulfide reagent-induced Ca2+ release were involved and that mibefradil did not release Ca2+ by inhibition of the Ca2+-ATPase pump of endoplasmic reticulum. The rate, but not the amplitude, of mibefradil-induced Ca2+ release is increased up to fourfold in the presence of pentosan polysulphate or heparin, two potent inhibitors of inositol 1,4,5-trisphosphate-induced Ca2+ release. Depletion of Ca2+ stores of permeabilized cells inositol 1,4,5-trisphosphate in the presence of thapsigargin completely blocked mibefradil-induced Ca2+ release, and depletion of Ca2+ stores by mibefradil prevented further Ca2+ release by inositol 1,4,5-trisphosphate. Mibefradil at supratherapeutic concentrations (> or = microM) thus mobilized Ca2+ from an inositol 1,4,5-trisphosphate-sensitive Ca2+ pool in cultured rat cardiac fibroblasts and human platelets.

Animals↗

PubMed1995

Decreased dihydropyridine receptor number in hypertensive rat vascular muscle cells.

To further investigate the altered function of Ca2+ channels in vascular muscle cells in hypertension, a novel fluorescently labeled dihydropyridine was used with ultrahigh-sensitivity photometry to study dihydropyridine binding sites on the surface membrane of living vascular muscle cells from stroke-prone spontaneously hypertensive rats and their normotensive controls. Fluorescent nitrobenzoxadiazol-6-dihydropyridine in concentrations of 1 to 100 nmol/L bound specifically to vascular muscle cells' Ca2+ channels, and was displaced by the unlabeled dihydropyridine analogue or nisoldipine (10 mumol/L). Stroke-prone spontaneously hypertensive rat vascular muscle cells showed significantly decreased binding of nitrobenzoxadiazol-6-dihydropyridine compared with normotensive National Institutes of Health rats. Decreased binding of dihydropyridine by vascular muscle cells from stroke-prone spontaneously hypertensive rats (cells that in other studies show increased Ca2+ channel function) indicates a change in channel regulation that is possibly due to a deficiency in the inactivation mechanism, consistent with our earlier electrophysiological studies reporting deficiencies in Ca(2+)-dependent inactivation in genetic hypertension. These data demonstrate decreased numbers of localized sites of dihydropyridine binding on the sarcolemma of living vascular muscle cells, and support the hypothesis that Ca2+ channel alterations may significantly contribute to the molecular etiology of genetic hypertension.

4-Chloro-7-nitrobenzofurazan↗

PubMed1994

Evidence against a functional ATP-dependent calcium extrusion mechanism in bovine epididymal sperm.

Bovine epididymal sperm resuspended in ionic buffers take up relatively large amounts of calcium. This uptake, which is almost entirely mitochondrial, apparently bypasses the sperm cytosol. The direct mitochondrial loading is an unusual aspect of sperm calcium uptake, which suggests that the plasma membrane region surrounding the mitochondria should be highly permeable to calcium, whereas the membrane domains surrounding the head and tail regions of sperm should be impermeable. This study was undertaken to determine the role of a plasma membrane calcium ATPase in sperm calcium homeostasis. Kinetics of calcium (45Ca2+) uptake into intact and permeabilized caudal epididymal sperm confirmed that mitochondrial calcium uptake occurs with virtually no resistance from the surrounding plasma membrane. Cytoplasmic calcium accumulation by sperm depleted of intracellular ATP, measured in the presence of mitochondrial calcium uptake inhibitors, showed no increase upon energy depletion as would be expected if an ATP-dependent calcium extrusion mechanism were present. Furthermore, lowering the incubation temperature to further reduce the activity of the calcium ATPase in these energy-depleted sperm was also without effect on calcium accumulation. The calcium ATPase inhibitor vanadate, even at high concentrations, failed to increase intracellular 45Ca2+ accumulation. However, vanadate was effective in inhibiting motility showing that the compound was accumulated into sperm to inhibit flagellar dyenin ATPase. Therefore, the lack of effect of vanadate on 45Ca2+ accumulation was not due to its inability to enter sperm. Other calcium ATPase inhibitors such as quercetin, thapsigargin, and cyclopiazonic acid, which readily demonstrate ATP-dependent calcium extrusion in other somatic cells, were also without effect on sperm calcium accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1994

Inhibition of signal Ca2+ in dog coronary arterial vascular muscle cells by Ro 40-5967.

The effects of Ro 40-5967, a chemically novel Ca2+ channel antagonist, were examined on K(+)- and norepinephrine (NE)-stimulated intracellular free Ca2+ concentrations in dog coronary artery vascular muscle cells (VMC). Intracellular Ca2+ activity increases stimulated by NE or K+ were measured by shuttered, low-intensity illumination with the fluorescent Ca2+ indicator fluo3 in single myovascular cells < or = 2 days after isolation. Pretreatment of VMC for 5 min with 10 microM Ro 40-5967 significantly reduced intracellular Ca2+ activity increase on exposure to 100 mM K+ in both subsarcolemmal (SSL) and central regions during K+ depolarization, similar to actions of diltiazem. More impressively, Ro 40-5967 (but not diltiazem) also reduced intracellular Ca2+ activity during stimulation with 100 nM NE to basal level at both peripheral and central regions. Prevention of Ca2+ increases, especially those caused by release from central Ca2+ stores, during NE stimulation is an unusual property for a Ca2+ antagonist, as shown by the contrast with diltiazem, which did not significantly attenuate Ca2+ increases during NE stimulation. Another Ro 40-5967 feature was vascular selectivity; i.e., Ro 40-5967 had only a minor effect on contraction frequency of rat myocardial cells while significantly inhibiting spontaneous contractions of rat spontaneously active VMC. In comparison, diltiazem and verapamil potently inhibited both vascular and cardiac muscle spontaneous contractions. The decidedly stronger actions of Ro 40-5967 as compared with those of benzothiazepine or phenylalkylamine on NE-stimulated Ca2+ increases, together with less action on cardiac pacemakers, are differences that appear to distinguish Ro 40-5967 from other Ca2+ antagonists.

Animals↗

PubMed1994

Aminoglycoside-induced increase of intracellular calcium in LLC-PK1 cells due to an artifact caused by trypsin and EDTA.

Dietary calcium supplements attenuate experimental aminoglycoside nephrotoxicity. In cultured renal tubular cells, intracellular calcium levels have been reported to rise with aminoglycoside addition to the culture medium. In experiments designed to verify the in vitro influence of calcium on cultured kidney cells, we detected an unexpected artifact. When we resuspended cultured LLC-PK1 cells with trypsin and EDTA to measure intracellular calcium levels, our results correlated well with previously reported values. However, we saw no increase in intracellular calcium levels when we measured them by digital imaging video microscopy unless trypsin-EDTA exposure preceded aminoglycoside exposure. This apparent artifact should be considered in any study of the effects of various agents on intracellular calcium levels.

Animals↗

PubMed1994

Selective inhibition of T-type Ca2+ channels by Ro 40-5967.

The present study shows that the chemically novel nondihydropyridine Ca2+ antagonist, Ro 40-5967, blocks T-type divalent ion currents in vascular muscle cells. T-type Ca2+ channels were blocked selectively and completely by therapeutic concentrations of 1 to 10 mumol/L Ro 40-5967, at which there was only 25% to 70% block of L-type Ca2+ currents. Using the combination of Ro 40-5967 and nisoldipine, a dihydropyridine selective for L-type Ca2+ channels, we found that all Ca2+ current could be completely blocked; thus, Ro 40-5967 is the first Ca2+ channel blocker to eliminate dihydropyridine-insensitive voltage-dependent Ca2+ current at therapeutically useful concentrations. The stepwise sequential block of T- and L-type Ca2+ currents demonstrated in the present study fulfills the functional criterion for the separate identity of the two Ca2+ channel types, and introduces a pharmacological tool that promises to be important in the exploration of T-type Ca2+ channel function.

Animals↗

PubMed1994

Resting state block and use independence of rat vascular muscle Ca++ channels by Ro 40-5967.

Blocking actions of the novel Ca++ antagonist, Ro 40-5967 ((1S,2S)-2-[2[[3-(2-benzimidazolylpropyl] methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-++naphthyl+ ++ methoxyacetate dihydrochloride), on divalent inward currents were characterized in spontaneously active vascular muscle cells (VMC) of neonatal rat azygos veins. Ca++ channel currents (ICa) were reduced by Ro 40-5967 in a concentration range from 0.1 to 10 microM, effective within the first 5 min of exposure. ICa were decreased by up to 70% during the first stimulus test pulse and remained constant during subsequent pulses, and were not shifted along the voltage axis, as determined by peak current-voltage plots. There was no change in apparent threshold or the voltage (+20 mV) at which maximum inward current occurred. Block of Ba++ currents through VMC Ca++ channels occurred independent of membrane potential, even when holding potential was as negative as -80 mV. ICa were blocked to the same absolute values from holding potential = -30 mV. Thus, ICa block occurred equally during the first pulse and at all subsequent time points, i.e., under conditions in which VMC Ca++ channels were in the resting state, inactive state, or open state. To search further for use-dependent effects of Ro 40-5967, we stimulated at higher frequencies (up to 0.3/sec), but there was no change in fractional block with frequency or stimulus repetition and thus no use dependence of the block of VMC Ca++ channels by Ro 40-5967.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Ca2+ channel actions of the non-dihydropyridine Ca2+ channel antagonist Ro 40-5967 in vascular muscle cells cultured from dog coronary and saphenous arteries.

We studied the membrane effects of (1S,2S)-2-(2-[[3-2(benzimidazolyl) propyl]methylamino]ethyl)-6-fluoro-1, 2,3,4-tetrahydro-1-isopropyl-2-naphthyl-methoxyacetate dihydrochloride, Ro 40-5967, a new non-dihydropyridine (DHP) Ca2+ channel antagonist, on dog coronary and saphenous arterial vascular muscle cells using the whole-cell patch-clamp method. Long-lasting (L-type) inward currents in 20 mM Ba2+ were measured over a range of test potentials (300 ms) from -50 mV to +90 mV from a holding potential of -80 mV in the presence of 1 microM Bay k8644 (a DHP Ca2+ agonist). Ro 40-5967 caused a concentration-dependent suppression of Ca2+ channel currents in muscle cells from both arteries, with greater potency on coronary than saphenous arterial cells. The concentration of Ro 40-5967 which inhibited the magnitude of peak inward currents by 50% (IC50) was estimated to be 1 microM (n = 5) in muscle cells from coronary artery and 10 microM (n = 4) in saphenous artery. Ro 40-5967 (1 microM) decreased the amplitude of the activation current-voltage relationship for coronary L-type Ca2+ channel currents over a wider range of membrane potentials than verapamil, diltiazem, or nifedipine. In contrast, block of Ca2+ channel currents in saphenous artery cells by 1 microM Ro 40-5967 was only observed at command potentials positive to 0 mV. Ro 40-5967 (1 microM) significantly shifted the voltage-inactivation curve downward by 40% in coronary (n = 4), but only by 18% in saphenous arterial muscle cells (n = 3).(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1993

Calcium channel function in hypertension.

Calcium channel function is fundamental to membrane excitation in vascular muscle, and imparts the notable voltage sensitivity to small blood vessels. The actions of the electrogenic sodium pump on membrane potential, and thus calcium channels, can explain perturbations that could alternately be conceived as acting on other mechanisms. Evidence for altered calcium channel function in hypertension suggests that deficiencies in function of the calcium channel per se lie at the root of altered membrane function. In this respect the disease may be similar to at least one form of skeletal muscle dysgenesis. Proportional increases in BP and Ca2+ current in vascular muscle of stroke-prone genetically hypertensive rats further strengthen this hypothesis of altered Ca2+ channel function in hypertension. Increased calcium in the subsarcolemmal space and several recently discovered substances that may endogenously modulate Ca2+ channels are additional evidence for abnormal Ca2+ channel function in BP regulation. From several kinds of evidence and multiple investigators, it is reasonable to conclude that calcium channel malfunction plays an important role in the vascular muscle contribution to hypertension.

Animals↗