Potential-operated Ca2 Research Articles

The calcium channel antagonist diltiazem effectively blocks two types of potassium channels in the neuronal membranes

Effect of the Ca2+-channel antagonist diltiazem on potential-operated Ca2+ and K+ currents was studied on isolated edible snail neurons by a two-microelectrode patch-clamp technique. Diltiazem in a concentration of 0.1 mM inhibits Ca2+ current, high-threshold Ca2+-dependent K+ current, and Ca2+-independent K+ current and has no effect on low-threshold K+ current and leakage current. It is suggested that therapeutic effect of diltiazem is mediated through blockade of Ca2+ and K+ channels.

Vascular Effects of Carvedilol, a New β-Adrenoceptor Antagonist with Vasodilating Properties, in Isolated Canine Coronary Artery

The pharmacologic properties of carvedilol, a beta-adrenoceptor antagonist with vasodilating activity, were investigated in isolated canine coronary artery ring preparations. Carvedilol competitively antagonized the relaxations caused by isoproterenol in 40 mM K+-depolarized preparations and its pA, value was 9.70 +/- 0.08. At concentrations greater than or equal to 3 x 10(-6) M, carvedilol significantly inhibited the contractile response to high [K+]o. Compared with the inhibitory effect on the KCl-induced contraction, the drug was less effective in suppressing the contraction induced by prostaglandin F2 alpha (PGF2 alpha). In addition, carvedilol (10(-7) to 3 x 10(-5) M) suppressed the contraction produced by Bay K 8644, a Ca2+ channel agonist. The concentration-response curve for Bay K 8644 was shifted downward by carvedilol in a concentration-dependent manner. The drug also produced a concentration-dependent inhibitory effect on the 4-aminopyridine-induced rhythmic contractions in a similar fashion to the Ca2+ channel antagonists. Carvedilol was ineffective in suppressing the contractions induced by PGF2 alpha in Ca2+-free solution and by A-23187. The results suggest that carvedilol exerts a vasodilating action possibly by inhibiting Ca2+ influx through potential-operated Ca2+ channels, although the concentrations required for producing the vasodilation are much higher than that for the beta-adrenoceptor antagonism in canine coronary artery.

Vascular Effects of Carvedilol, a New β-Adrenoceptor Antagonist with Vasodilating Properties, in Isolated Canine Coronary Artery

Summary: The pharmacologic properties of carvedilol, a β-adrenoceptor antagonist with vasodilating activity, were investigated in isolated canine coronary artery ring preparations. Carvedilol competitively antagonized the relaxations caused by isoproterenol in 40 mM K+ -depolarized preparations and its pA, value was 9.70 ± 0.08. At concentrations ≥3 × 10−6M, carvedilol significantly inhibited the contractile response to high [K+]o. Compared with the inhibitory effect on the KCI-induced contraction, the drug was less effective in suppressing the contraction induced by prostaglandin F2α (PGF2α). In addition, carvedilol (10−7 to 3 × 10−5M) suppressed the contraction produced by Bay K 8644, a Ca2+ channel agonist. The concentration-response curve for Bay K 8644 was shifted downward by carvedilol in a concentration-dependent manner. The drug also produced a concentration-dependent inhibitory effect on the 4-aminopyridine-induced rhythmic contractions in a similar fashion to the Ca2+ channel antagonists. Carvedilol was ineffective in suppressing the contractions induced by PGF2α in Ca2+-free solution and by A-23187. The results suggest that carvedilol exerts a vasodilating action possibly by inhibiting Ca2+ influx through potential-operated Ca2+ channels, although the concentrations required for producing the vasodilation are much higher than that for the β-adrenoceptor antagonism in canine coronary artery.

Mechanism of adenosine receptor-induced renal vasoconstriction in rats

Adenosine analogues selective for the A1 subclass of adenosine receptors, such as N6-cyclohexyladenosine (CHA), induce vasoconstriction in the isolated rat kidney perfused at constant flow. Presumably, the vasoconstriction is mediated by increased Ca2+ concentration in renal vascular smooth muscle cells, but the mechanism by which A1 adenosine receptor occupation leads to increased Ca2+ is unknown. In the present experiments, the isolated, perfused rat kidney vasoconstricted in response to CHA, to K depolarization, and to BAY K 8644 (a Ca2+ channel agonist). All of these responses were completely blocked by methoxyverapamil, which suggests that CHA, like K depolarization and BAY K 8644, induces renal vasoconstriction by increasing Ca2+ influx through potential operated Ca2+ channels. The mechanism of action of CHA was different, however, in that pertussis toxin treatment blocked the response to CHA without affecting the responses to K depolarization or to BAY K 8644. Therefore, a pertussis toxin-sensitive step must intervene between occupation of A1 adenosine receptors on renal vascular smooth muscle cells and increased Ca2+ influx through potential-operated Ca2+ channels.

Pharmacological Profile of Vasodilating Action of Carvedilol in Isolated Canine Coronary Artery

Carvedilol is a new ,a-blocking agent that also possesses vasodilating properties (Sponer et al. 1987). Clinical studies confirm its efficacy in the treatment of hypertension and angina and indicate that carvedilol may have a significant advantage over standard ,8-blockers (Eggertsen et al. 1984; Heber et al. 1987; Kaski et al. 1985; Lahiri et al. 1987; Rodrigues et al. 1986). However, the mechanism by which carvedilol exerts vasodilatation remains to be established. The objective of this study was to examine the pharmacological effects of carvedilol on isolated canine coronary artery. The left circumflex coronary artery rings were isolated from dogs and mounted for isometric tension measurement by methods described previously (Hattori et al. 1986). The rings were allowed to equilibrate for 1 hour in the bathing solution. After the accommodation period , the preparations were tested either by exposing to 40 mmol/L K+ or by adding 10 Jlmol/L PGF2" until the response to either agent became constant, and then the experiments were commenced. Carvedilol competitively antagonised the relaxation induced by isoprenaline in the preparations precontracted with 40 mmol/L K+, and its pA2 value was 9.70 ± 0.08 (n = 8). The pA2 value of propranolol was 8.82 ± 0.14 (n = 6); thus, carvedilol was more potent than propranolol in blocking the coronary ,a-adrenoceptors. Carvedilol at concentrations greater than 3 Jlmol/L was found to inhibit significantly the contractile response to high potassium (K+). The inhibitory effect of carvedilol on the KCl-induced contractions was more prominent than its effect on the response to PGF2", Furthermore, carvedilol (0.1-30.0 Jlmol/L) relaxed the rings precontracted with the Ca2+ channel agonist Bay K 8644. The concentration-response curve for the contractile response to Bay K 8644 was shifted downwards by pretreatment with carvedilol in a concentration-dependent manner. The drug also caused a concentration-dependent inhibitory effect on the rhythmic contractions produced by 10 mmol/L 4-aminopyridine in a similar way to the well-known Ca2+ channel antagonists such as verapamil and cinnarizine. On the other hand, carvedilol was ineffective in suppressing the contractions induced by 20 Jlmol/L PGF2" in Ca2+-free physiologicalsalt solution and by 5 Jlmol/L A23187, a Ca2+ ionophore. These results indicate that carvedilol can exert a vasodilating action, possibly by inhibiting Ca2+ influx through potential-operated Ca2+ channels. However, the concentrations of carvedilol required to produce the direct vasodilating activity are much higher than those required for its ,a-blockingaction.

Pharmacological characteristics of receptor-operated and potential-operated Ca2+ channels in rat aorta

In the rat aorta activation of the potential-operated Ca2+ channels by 100 mM K+ resulted in a greater 45Ca2+ influx than stimulation of the receptor-operated Ca2+ channels by norepinephrine (NE, 3 X 10(-7) M) or angiotensin II (AII, 10(-7) M). 45Ca2+ influx induced by NE was inhibited by prazosin (10(-7) M) but not by yohimbine (10(-6) M) while that by AII was abolished by [Sar1, Ile8]AII (10(-8) M). These receptor antagonists had no effect on the 45Ca2+ influx produced by K+. Bay k 8644 enhanced the influxes to low concentrations of NE and K+ while it was additive with the maximal concentration of NE but not with K+. 3-Isobutyl-1-methyl-xanthine and forskolin inhibited both the influx and efflux of 45Ca2+ elicited by NE but were ineffective against those caused by K+. Nifedipine blocked the efflux of 45Ca2+ induced by K+ but not that evoked by NE. However, both types of Ca2+ channel exhibited the same sensitivity to inhibition by Ca2+ entry blockers (nifedipine/verapamil) on 45Ca2+ influxes. These data suggest that in the rat aorta, the receptor-operated calcium channels and potential-operated calcium channels share similar structural characteristics. However, they are gated separately and distinctly by their respective activators.

Experimental diabetes: reduction of serotonin-induced vasoconstriction by meclofenamic acid in vitro.

In diabetes the sensitivity of isolated rat aortae to serotonin is greatly diminished and the dose-response curve is shifted to the right. The maximal response is reduced to 37% of control, the threshold dose is approximately tenfold greater, and the ED50 is about fourfold greater than control. This decrease in sensitivity may be due, in part, to a reduction in the synthesis of prostaglandins because serotonin-induced responses in normal and diabetic arteries treated with meclofenamate are also significantly diminished. In addition, there is evidence that both receptor-operated Ca2+ and potential-operated Ca2+ channels may be impaired because the responses to norepinephrine and KCl are both dampened in diabetic aortae. The greatly diminished effect of serotonin may be a sensitive tool to study the nature of diabetes better and to monitor its development.

Mechanisms of action of transmitters and other substances on smooth muscle.

Mechanisms of action of transmitters and other substances on smooth muscle.