Calcium channel blockers, that is, XX dipalion, by blocking vascular smooth troponium channels, dilate peripheral blood vessels, reduce blood pressure, is a large class of basic drugs in antihypertensive therapy, widely used in clinical practice. To date, most of the calcium channel blockers commonly used in clinical practice are acting (or basically) on a single L-type calcium channel, which can be accompanied by adverse effects such as reflex sympathetic activation, ankle edema and hyperperfusion of glomeruli while effectively lowering blood pressure.
The new generation of calcium channel blockers benidipine, nicardipine, and sinidipine are long-acting membrane-mediated calcium channel blockers, which can act on three subtypes of calcium channels of L, T and N at the same time, and the antihypertensive effect is stable, the effect is strong and lasting, and it can effectively overcome the adverse reactions caused by a single L-type channel block, and at the same time has cardiovascular and cerebrovascular benefits other than antihypertensive.
First, the unique three-channel block and membrane-mediated pharmacological properties make it have a strong, stable and long-lasting antihypertensive effect
Traditional calcium channel blocker drugs mainly achieve the effect of vasodilation and blood pressure reduction by blocking L-type calcium channels; benitipine simultaneously blocks vascular smooth muscle L and T double subtype calcium channels, making the vasodilation effect stronger, so that the antihypertensive effect is also enhanced. At the same time, benitipine has a high degree of fat solubility and high membrane affinity, which is easier to enter and store in a high concentration in a phospholipid-rich cell membrane, and slowly binds to the voltage-dependent calcium channel of the cell membrane, and its dissociation rate is slower after binding to the dihydropyridine site of the cell membrane calcium channel.
Therefore, when the plasma drug concentration is very low, or even undetectable, the drug molecule stored in the cell membrane can still continue to migrate in the membrane and combine with the calcium channel to play its blocking effect, which is the membrane-mediated long-acting effect, which clinically shows a sustained long-acting and stable antihypertensive effect, and does not rely on the effect advantage of plasma drug concentration.
Second, it has a high degree of fat solubility and membrane affinity, stronger and more durable relaxation of coronary blood vessels, and increased myocardial blood supply and oxygen supply
Benidipine has a high degree of fat solubility and high membrane affinity, which is easier to enter the vascular endothelial cell membrane, and also has a high affinity for the dihydropyridine binding site, which makes it bind to the vascular endothelial cell membrane and slow dissociation speed, so its selectivity to blood vessels is higher and more durable than other level calcium channel blockers.
In the canine in vivo coronary arteries, the inhibitory effect of different calcium channel blockers on potassium chloride-induced vasoconstriction was studied, and it was found that low concentrations of benidipine inhibited vasoconstriction for a long time. Another study found that the vascular selectivity index of benitidipine was 14.4 times that of nifedipine and 19 times that of amlodipine, that is, benitidipine had a stronger coronary diastolic effect and weaker negative myocardial inotropic effect than amlodipine and nifedipine.
Third, inhibit the sympathetic nervous system and sinus nodes, reduce myocardial oxygen consumption, and have little impact on heart rate
Single L-type calcium channel block can be accompanied by reflex sympathetic activation while relaxing blood vessels, and clinically there are often adverse reactions such as increased heart rate, flushing of face, headache, etc., while benidipine can simultaneously block N-type calcium channels, inhibit the release of sympathetic peripheral neurotransmitters, and inhibit sympathetic activation, thereby avoiding increased heart rate reflex, avoiding the above adverse reactions, and also conducive to the overall treatment of hypertension.
In addition, there are T-type calcium channels in the heart, which have a high density in myocardial growth and conduction cells, and the T-type calcium channels can be activated when they are close to the rest potential, so they are of great significance for maintaining the autonomy of the myocardium; the blocking of the T-type calcium channels by benitipine can reduce the automatic polarization slope of the sinus node 4 phases (4 phases calcium inflow decrease) and slow down the heart rate.
4. Equally dilate the glomerular entry and exit of glomerular arterioles, improve the hyperperfusion status of glomeruli, protect renal function, and reduce cardiovascular events
Renal function is closely related to the occurrence of cardiovascular events. The distribution density of L-type calcium channels on the smooth muscle of glomerular insular arterioles is significantly higher than that of the bulbous arterioles, so after using traditional level calcium channel blockers, the expansion of the glomerular arterioles is greater than that of the effusion arterioles, causing a hyperperfusion state of the glomeruli, and the transmembrane pressure of the glomerular capillaries is increased, and the direct consequence of the latter is an increase in the rate of urinary albumin excretion and increases proteinuria.
At the same time, due to the increase in transmembrane pressure, it can cause glomerular pathological structural remodeling, thickening of the mesangial matrix, renal interstitial fibrosis, and promote the progression of renal insufficiency. The T-type calcium channel is distributed on both the incisor and outflow arterioles of the glomeruli, and the distribution density of the glomerular arterioles is higher than that of the glomerular arterioles, so that the transmembrane pressure of the glomerular capillaries can be reduced or balanced, and the proteinuria is reduced or not increased, which is conducive to protecting renal function.
In short, like benedipine, nicardipine, sinidipine this type of calcium ion 3-channel blocker, compared with the traditional horizon only blocks the calcium channel of vascular smooth muscle, the antihypertensive effect is more intense and stable and lasting, improve myocardial ischemia stronger, but also reduce myocardial oxygen consumption, almost do not affect the heart rate, has a better renal protective effect.