Vascular effects of betaxolol, a cardioselective .BETA.-adrenoceptor antagonist, in isolated rat arteries.

Abstract

ABSTRACT-The effects of betaxolol on isolated rat arteries and the modes of action were investigated. Betaxolol (10-5 -10-3 M) relaxed the 80 mM K+-induced contrac tion of aortic strips concentration-dependently. The 50% inhibitory concentration of betaxolol in the K+-induced contraction was 3 times higher than that of papaverine and about 3 times lower than that of bunitrolol. The relaxations by betaxolol were also demonstrated in renal, mesenteric and femoral arteries. Betaxolol (3 X 106 M 10-4 M) produced rightward parallel shifts of the concentration-response curves for Ca 2+ in the K+-depolarized aortic strips. On the other hand, betaxolol produced downward shifts as well as rightward shifts of the concentration-response curves for norepinephrine, 5-HT and angiotensin II. In K+-depolarized aortic strips, the cyto solic Ca 2+ concentration measured with a fluorescent indicator, fura-2, was decreased by betaxolol (10-4 M) almost concomitantly with the loss of tention. An elevation of external Ca 2+ from 2.5 mM to 10 mM restored both the cytosolic Ca2+ concentration and tention. The relaxations of arteries induced by betaxolol were not influenced by glybenclamide, methylene blue, indomethacin or removal of the endothelium. These results suggest that betaxolol possesses a direct vasodilating action, and the action may be due to the inhibition of Ca 2+ influx across the cell membrane. Betaxolol [(±)-1-[4-[2-(cyclopropylmethoxy) ethyl]phenoxy]-3-(isopropylamino)-2-propanol]hydrochloride is a cardioselective ,Q-adreno ceptor antagonist with no intrinsic sympatho mimetic activity and little membrane stabiliz ing activity (1, 2). In patients with essential hypertension, betaxolol was shown to produce potent and long lasting antihypertensive effects by once daily therapy (2, 3) because of high bioavailability and a long elimination half life (4, 5).In previous laboratory studies, we (6-8) and other workers (9) have shown that a single oral administration of betaxolol lowers the blood pressure of various hypertensive models, i.e., spontaneously hypertensive rats, renal hypertensive rats, deoxycorticosterone/ saline hypertensive rats and renal hypertensive dogs. However, other 8-adrenoceptor anta gonists such as atenolol are unlikely to pro duce antihypertensive effects by single admin istration in these hypertensive models (10 13). These data suggest that betaxolol might have a certain effect other than 8-adreno ceptor antagonism. In fact, betaxolol induced an increase in blood flow by intraarterial administration (6) and a decrease in total peripheral resistance by intravenous adminis tration in anesthetized dogs (14).Although / -adrenoceptor antagonism of be taxolol has been well studied (2), the effects of betaxolol on isolated arteries have not yet

Contrasting effects of betaxolol and propranolol on Ca2+-activated contractions in skinned fibers from canine coronary arteries and ventricular muscles

“…The effects of betaxolol and propranolol were observed in the same range of concentrations (10 -5 to 10 -3 M) and (10 -4 to 10-~M), respectively, that produced the decrease in both the developed tension and the intracellular Ca 2 concentration in K+-depolarized rat aorta strips [6]. These results indicate that vasorelaxation of betaxolol and propranolol may be due, at least in part, to inhibition of Ca 2÷ influx into smooth muscles.…”

“…Bessho et al [6] have found that betaxolol has a Ca 2+ antagonistic property in smooth muscle, although this effect of betaxolol was weaker than that of diltiazem. Betaxolol has a less potent negative inotropic action when compared with atenolol and propranolol in dog heart [7].…”

Glaucoma, Capillaries and Pericytes

“…Therefore, iso proterenol-induced relaxation in pericytes, as in adrenocep tor-mediated relaxation of vascular smooth muscles [13][14][15], is most likely due to the P-adrenoceptor-coupled ade nylate cyclase activation, which increases the intracellular concentration o f cAMP. It is known that some P-agonists and P-antagonists in high dosage have calcium channel blocker effects that might affect contractile tone in smooth muscle [16,17], but this effect has not been confirmed in pericytes.…”

Medications Used to Treat Glaucoma

“…There is some evidence that betaxolol may increase retinal and choroidal blood flow by acting on voltage-dependent calcium channels. 102,[106][107][108][109][110][111][112][113][114][115] It may thus have some neuroprotective effect separate from its IOP lowering properties. 116,117 Levobunolol has an active metabolite (dihydrobunolol) that may contribute to its longer duration of activity when compared with timolol.…”