Biomedical subjects

K Hermsmeyer

Publications and source records attributed to K Hermsmeyer.

96 records · Page 6Linked to original sources

PubMedDate not supplied

Glyburide actions on the dihydropyridine-sensitive Ca2+ channel in rat vascular muscle.

The effects of glyburide, a purportedly selective ATP-sensitive K+ channel antagonist, were studied on dihydropyridine (DHP)-sensitive (L-type) Ca2+ channel currents in rat aortic muscle cells. Whole-cell voltage-clamp Ba2+ currents (IBa) were recorded at a series of test potentials (VT) from -30 to +60 mV during 300-ms voltage steps from a holding potential of -80 mV. Bay k8644 (1 microM) increased peak divalent cation currents from 47.2 +/- 15.1 to 102.6 +/- 13.4 pA, and the current-voltage relationship curve was shifted 10 mV to the left (n = 5). The combination of 10 microM glyburide with 1 microM Bay k8644 further increased Bay k8644-enhanced IBa in each cell (average of 223.7 +/- 26.4 pA, n = 5), and caused a further 10 mV hyperpolarizing (leftward) shift of the activation curve. The kinetics of IBa were also changed (more rapid inactivation) by glyburide. These stimulatory actions of glyburide were reversed on washout. In contrast to this apparent synergism with Bay k8644, 10 microM glyburide alone inhibited (rather than potentiated) IBa by about 20% at VT of 0, +10, and +30 mV. Increasing glyburide concentration to 30 microM further inhibited the IBa to about 40-50% of controls. With the pure agonist isomer, 0.5 microM Bay R5417, at theoretically the same concentration of the minus enantiomer as is present in Bay k8644, IBa increased from 137 +/- 18.3 pA to 354.2 +/- 12.4 pA (n = 4).(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMedDate not supplied

Stroke-prone SHR vascular muscle Ca2+ current amplitudes correlate with lethal increases in blood pressure.

Studies on the possible causal relationship between the Ca2+ channel current density in the vascular muscle cell (VMC) and increases in blood pressure were extended by a comparison of stroke-prone spontaneously hypertensive rats (SP-SHR) with N/nih outbred normotensive rats. Maximal amplitudes of both L-type and T-type Ca2+ channel currents were significantly increased in SP-SHR without a difference in cell capacitance. SP-SHR peak current amplitudes in 20 mM Ba2+ averaged 446 +/- 64 pA while N/nih averaged 156 +/- 25 pA (clearly separated statistically). Both L-type and T-type Ba2+ currents (IBa) were significantly increased in SP-SHR, shown also by peak current frequency distributions. There was a significant shift to the left of both activation (7 mV) and inactivation (15 mV) current-voltage (I-V) plots. SP-SHR IBa recovery from inactivation was significantly slower (103 versus 61 ms) than in N/nih VMC. The increases in SP-SHR IBa amplitude under maximized conditions correlated with increases in blood pressure. Together with earlier observations of increased vascular muscle Ca2+ current density coexistent with blood pressure elevation in Kyoto-Wistar SHR, these data provide evidence for altered function of Ca2+ channels as a fundamental component of hypertension. Since the Ca2+ channel alterations exist in venous VMCs of newborn SP-SHR rats (in a low pressure blood vessel and at a time when increased Ca2+ current density could not be an effect of increased blood pressure), our results add to the growing evidence of Ca2+ channel abnormalities as a cause of genetic hypertension.

Animals↗

PubMedDate not supplied

Protein kinase C mechanism enhances vascular muscle relaxation by the Ca2+ antagonist, Ro 40-5967.

Actions of the novel Ca2+ antagonist, Ro 40-5967, which displays unusual efficacy against endothelin (ET)-induced contractions, were studied in isolated vascular muscle cells (VMCs) using the fluorescent protein kinase C (PKC) indicator, BODIPY 12 alpha-phorbol ester 13 beta-acetate (PBA-BODIPY). High-sensitivity (photon-counting) digital-imaging microscopy quantified PKC distribution within VMCs and showed translocation from the cytosol to the cell surface membrane on stimulation with ET. ET (1 nM) stimulated translocation of PBA-BODIPY fluorescence that peaked at 4 min, increasing from 19 +/- 2% to 29 +/- 2% surface membrane (edge) distribution (n=44, p<0.05). Increases in membrane-associated PKC due to translocation began within 2 min and persisted for about 10 min, after which a gradual decline to control levels occurred. Upon exposure to Ro 40-5967 (10 microM), there was an inhibition of fluorescence intensity throughout the cell. Average fluorescence intensity decreased to 84 +/- 4% (n=20, p<0.05) of that in prestimulus controls. Cell/membrane was also reduced to below unstimulated control levels. Amlodipine failed to decrease PKC fluorescence intensity or translocation to the surface membrane. These data suggest that there is an important direct PKC inhibitory action of Ro 40-5967 that would at least partially explain relaxation of ET-induced contractions.

Animals↗

PubMedDate not supplied

Effect of cross-transplantation on normotensive and spontaneously hypertensive rat arterial muscle membrane.

Transplantation of arteries into the anterior eye chamber of rats for 8 weeks was used to test the hypothesis that the neurohumoral environment is important in establishing the altered membrane potential (observable during electrogenic ion transport inhibition) of vascular muscle in hypertension. When caudal arteries from 12- to 16-week-old spontaneously hypertensive rats (SHR) or genetically matched Kyoto-Wistar normotensive rats (KNR) were transplanted into the opposite strain, there was no change in the transport inhibited membrane potential (Em) of the arterial muscle cells from that found in freshly excised donor arteries. However, when caudal arteries from 2-week-old animals were transplanted into the anterior eye chamber, the arteries always developed the appropriate Em for the host animal. In other words, a genetically KNR artery developed the Em of an SHR artery in an SHR host; conversely, a genetically SHR artery developed the Em of a KNR artery in the KNR host. These results provide evidence that: 1) the differences between th Em of caudal arteries from SHR and KNR are not inherent in those muscle cells; 2) the change in Em is triggered in young animals preceding development of hypertension, but not after hypertension is established; and 3) the Em alteration of the caudal artery is independent of structural changes that occur in the artery as a result of increased blood pressure (because KNR transplants were not connected in series with the host anterior eye chamber vasculature and subject to the elevated blood pressures). We conclude that the arterial muscle cells up to a certain age respond to an external factor that regulates their Em and presumably their sensitivity to vasopressor agents.

Animals↗

PubMedDate not supplied

Membrane mechanisms in arterial hypertension.

The purpose of this review is to focus on alterations in vascular muscle membrane potentials (Em), ionic permeabilities, and ionic transport systems which may either contribute to or be a consequence of the hypertensive state. Three models of hypertension are discussed: 1) deoxycorticosterone-salt (DOCA-salt)-induced hypertension; 2) low-renin (presumably volume expanded) renal hypertension (LRRH); and 3) the spontaneously hypertensive rat (SHR) of the Okamoto-Aoki Kyoto-Wistar strain and its normotensive genetic control (WKY). The importance of studying all possible mechanisms of increased contraction in vascular smooth muscle is stressed.

Animals↗

PubMedDate not supplied

Norepinephrine sensitivity and membrane potentials of caudal arterial muscle in DOCA-salt, Dahl, and SHR hypertension in rat.

Comparison of norepinephrine (NE) sensitivity in caudal arterial muscle of rats with three forms of hypertension showed that there was no increase in either DOCA-salt or Dahl genetic hypertension, in contrast to the increased NE sensitivity found in spontaneously hypertensive rats (SHR). In hypertension induced by deoxycorticosterone acetate (DOCA)-salt treatment, as in Dahl genetic hypertension, there was also no difference in membrane potential (Em) between hypertensive and normotensive rats. By comparison to the SHR membrane alterations reported previously, any increased NE sensitivity might have been associated with altered Em electrogenesis which is triggered by a trophic factor of the sympathetic nervous system. SHR have a lower intracellular K+ free ion concentration and thus a smaller contribution of the ion gradient generated voltage which appears to be compensated for at rest by more active electrogenic ion transport. While SHR show greater depolarization and contraction than Wistar-Kyoto (WKY) rats in response to midrange NE concentrations, DOCA-salt and Dahl hypertensive rat caudal arterial muscle showed neither NE hypersensitivity nor any evidence of altered Em mechanisms. Ion transport in isolated peripheral arteries in DOCA-salt hypertension may only secondarily be altered in response to primary changes in humoral factors and altered neural control mechanism.

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