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Although the mechanism of antihypertensive action of beta-adrenergic blocking drugs (beta-blockers) is not known, a theoretical advantage of cardioselective beta-blockers over nonselective ones has been proposed in the treatment of hypertension. To study this hypothesis, we examined cardiovascular responses to handling stress in spontaneously hypertensive (SHR) rats after a single (100 mg/kg) and multiple oral treatments (100 mg/kg per day for 17 d) with either atenolol or propranolol. Atenolol and propranolol markedly suppressed the tachycardia induced by handling stress after acute and chronic administration. Resting mean arterial pressure (MAP) was reduced by acute and chronic atenolol treatment, but not by propranolol. Stress-induced increase in MAP was significantly reduced by chronic treatment with propranolol, whereas no consistent effects were observed with atenolol. Acute treatment with guanethidine (30 mg/kg) markedly reduced the rise in MAP induced by stress. These results suggest that suppression of cardiac function by beta-blockers does not always attenuate the rise in MAP induced by stress, thus cardioselective beta-blockers might not confer any further reduction of the blood pressure increase due to sympatho-adrenal excitation. Inhibition of stress-induced MAP rise by propranolol could be mediated by a modulation of the catecholamine release.

A hypothesis that the beta-adrenergic blocking drugs may possess weak alpha-adrenergic blocking activity, and that their antihypertensive effect may be due to this combined alpha - and beta-adrenergic blockade was tested. Phenoxybenzamine (PBZ) and propranolol (PPL) were selected as alpha - and beta-blocking drugs, respectively. They were given orally at doses of 1--100 mg/kg per day, 5 days per week. Their combined antihypertensive effects were determined in spontaneously hypertensive; deoxycorticosterone and salt hypertensive; and two kidney, one clip renal hypertensive rats. PBZ treatment showed antihypertensive effect in three models of hypertensive rats. However, addition of PPL either did not affect or rather antagonized the effect of PBZ. Moreover, the combined treatment increased side-effects, typically seen as urinary incontinence. The results did not support the above hypothesis, at least when the blockade was caused with PBZ and PPL.

We have devised a simple method to determine the ratios of cardiac to vascular beta-receptor blockage (C:V ratios) in normotensive rats anesthetized with pentobarbital, and applied it to six beta-adrenergic blocking drugs (beta-blockers). Mean blood pressure (BP) and heart rate (HR) were recorded. Isoproterenol (3 ng-100 microgram/kg, i.v.) was cumulatively injected before and after the intravenous administration of beta-blockers at two dose-levels. Thus shifts of the dose-response curves in BP and HR were observed. "In vivo pA2" values were calculated in molar doses per kg by Schild plots. The C:V ratio was calculated as antilogarithm of the difference of the mean in vivo pA2 value in HR from that in BP. Those of atenolol, bometolol, bunitrolol, pindolol, propranolol, and sotalol were 9.77, 8.13, 2.95, 1.38, 1.20, and 0.71, respectively.

Ratios of cardiac to vascular beta-receptor blockade (C:V ratios) of atenolol and propranolol were determined in pentobarbital anesthetized spontaneously hypertensive (SHR) rats. These values and the cardiovascular responses to isoproterenol were compared with those of age-matched normotensive control (Donryu, DON) rats reported previously. Mean blood pressure (BP) and heart rate (HR) were recorded. Full dose-response curves for isoproterenol were constructed in BP and HR. In vivo pD2 values of isoproterenol (potencies), were not different between DON and SHR rats, although the maximal responses to isoproterenol (efficacy) were significantly suppressed in SHR rats. C:V ratios of atenolol and propranolol in SHR rats were 7.95 and 0.44, respectively. As the values in DON rats were 9.77 and 1.20, respectively, C:V ratios of atenolol and propranolol were decreased in SHR rats. Markedly decreased C:V ratios of propranolol in SHR rats may explain its relatively weak antihypertensive action.

Antihypertensive effects of three beta-adrenergic blocking drugs, acebutolol, propranolol, and practolol were studied for 11 weeks. Spontaneously (SHR); one-clip, two-kidney (CLIP); and deoxycorticosterone and salt (DOC) hypertensive rats were used. The drugs were given orally, 100 mg/kg per day, 5 days per week before development of hypertension. Propranolol inhibited blood pressure (BP) increase significantly in SHR. Acebutolol and practolol also lowered BP in SHR. Three drugs did not affect BP in CLIP, but an apparent inhibition was seen when the results were analyzed including the cases of which BP stayed below 150 mmHg. Either of three drugs did not show antihypertensive effects in DOC. Acebutolol rather increased BP more rapidly. Practolol also increased BP slightly more rapidly. Cerebral stroke was seen in DOC. The incidences of the stroke in the groups given the solvent, acebutolol, propranolol, and practolol were 3/6, 4/7, 2/6, and 3/6, respectively. Acebutolol seemed to cause stroke earlier with the more rapid BP elevation. Acebutolol, propranolol, and practolol decreased incidence of the vascular disease in CLIP. Propranolol also decreased it in DOC. Plasma renin activity was suppressed by these drugs in SHR and CLIP. The mechanisms of antihypertensive effects of beta-adrenergic blocking drugs are unknown. The present study denies those due to inhibition of cardiac function, or renin release from the kidney. A better experimental model is necessary to study this. The possibility that acebutolol and other beta-blockers might accelerate BP elevation and incidence of stroke must be reexamined.

Arotinolol (S-596, ARL) is a beta-adrenoceptor blocking drug with weak alpha-adrenoceptor blocking activity, and may be classified into the fourth generation. Antihypertensive effects of ARL were studied for 12 weeks in spontaneously hypertensive (SHR) rats. Propranolol (PPL) was used as the reference drug. ARL (20 and 100 mg/kg per day, p.o.) and PPL (100 mg/kg per day, p.o.) treatments significantly decreased heart rate, within a week after the drug treatments had started and thereafter. Tail blood pressure (BP), determined by prewarming the rat at 50 degrees C for 3 min, was slightly higher in the two ARL treated groups than in the control. Tail BP was slightly lower in the PPL treated group than in the control. Mean BP determined directly at the 12th week was lower in the two ARL and PPL groups than in the control by more than 20 mmHg. Both ARL (100 mg/kg per day) and PPL (100 mg/kg per day) treatments significantly reduced incidences of the vascular lesions, and also prevented the decrease of kidney weights usually associated with mild vascular lesions. Furthermore, these treatments showed a tendency to decrease plasma renin (PRC) and aldosterone (PAC) concentrations determined 20 h after the last administration. As mean BP must be more reliable than tail BP, it was concluded that ARL (20 and 100 mg/kg per day) showed almost the same chronic antihypertensive activity in SHR rats as PPL (100 mg/kg per day). Preventive effects of ARL on development of vascular lesions also supported the above view.

Bometolol is a cardiospecific beta-adrenergic blocking drug. The effect on blood pressure was determined in hypertensive rats in acute and subchronic experiments. In acute experiment bometolol, 10-30 mg/kg, p.o., was given to spontaneously hypertensive rats; deoxycorticosterone and salt hypertensive rats; and two kidney, one clip hypertensive rats. Blood pressure was determined continuously for 8 h and after 24 h in unanesthetized condition. The blood pressure lowered by bometolol was dose-dependent in three types of hypertension. In subchronic experiment, bometolol at a dose of 10-30 mg/kg or 100-300 mg/kg, p.o., were given for 5 weeks to deoxycorticosterone and salt hypertensive rats; and two kidney, one clip hypertensive rats. Bometolol did not show antihypertensive effect in either type of hypertension, although bometolol decreased heart rate dose-dependently. Bometolol treatment at the above doses decreased plasma renin activity, heart and kidney weights, and incidence of vascular lesion in either hypertensive rat. Toxic symptom was seen 3 days after bometolol treatment of 300 mg/kg in deoxycorticosterone and salt hypertensive rats.

4-[3-(tert-Butylamino)-2-hydroxypropoxy]-N-methylisocarbostyril hydrochloride (N-696) is a new beta-adrenoceptor blocking drug with direct vasodilatory activity, and may be classified into the fourth generation. Antihypertensive effects of N-696 were studied for 12 weeks in spontaneously (SHR), two kidney, one clip (CLIP), and deoxycorticosterone-salt (DOC) hypertensive rats. Propranolol (PPL) was used as the reference drug. In indirect blood pressure (BP) determination at the tail, milder prewarming condition was employed to observe antihypertensive effects clearly. Rats were prewarmed in rat holders on a hot plate for 30-60 min. Surface temperature of the hot plate was 35-45 degrees C. N-696 (20 mg/kg per day p.o.) and PPL (100 mg/kg per day, p.o.) treatments significantly decreased heart rate (HR) and maximum BP determined indirectly in SHR rats, even at the early stage of the experiments. These antihypertensive effects were shown also by mean BP determined directly at the 12th week. N-696 and PPL treatments showed no significant antihypertensive effects in CLIP rats, and slight antihypertensive effects in DOC rats. N-696 treatments showed a tendency to decrease plasma renin concentration (PRC) in SHR and DOC rats, whereas PPL treatments significantly decreased PRC in these hypertensive rats. N-696 and PPL treatments prevented nephrosclerosis and vascular lesions in SHR and DOC rats only slightly.