Martin J.M.C. Thoolen

SGD 101-75 IS DISTINGUISHED FROM OTHER SELECTIVE ALPHA-1-ADRENOCEPTOR AGONISTS BY THE INHIBITION OF ITS PRESSOR-RESPONSES BY CALCIUM ENTRY BLOCKADE AND VASODILATATION IN PITHED RATS AND CATS

The vasopressor effects of the selective alpha 1-adrenoceptor agonist Sgd 101/75 (2-[2-methylindazol-4-imino]-imidazolidine HCl) were analyzed in pithed rats and cats. Vasodilatation by the beta 2-adrenoceptor agonist salbutamol (1 mg/kg i.v.) or by the converting enzyme inhibitor captopril (5 mg/kg i.v.) antagonized the vasoconstriction by Sgd 101/75 in pithed rats. The effect of salbutamol was abolished by restoration of the baseline diastolic pressure by infusion of vasopressin. Calcium entry blockade by nifedipine (0.1-3 mg/kg i.v.) and (-)-verapamil (0.3 and 1 mg/kg i.v.) dose dependently inhibited the rise in the diastolic pressure induced by Sgd 101/75 pithed rats. This inhibition could not be attenuated by an infusion of vasopressin. In pithed cats, nifedipine most effectively antagonized the pressor effects of Sgd 101/75. In this respect, Sgd 101/75 is different from other alpha 1-adrenoceptor agonists, which are known to elicit a vasoconstriction which is virtually insensitive to vasodilatory measures and calcium entry blockade. These findings may be explained on the basis of a further subdivision of vascular postjunctional alpha 1-adrenoceptors.

The contractions induced in rat and guinea-pig aortic strips by the α2-adrenoceptor selective agonists B-HT 920 and UK 14,304 are mediated by α1-adrenoceptors

The alpha-adrenergic action of the selective alpha 2-adrenoceptor agonists B-HT 920 and UK 14,304 was investigated on helically cut preparations of rat and guinea-pig isolated aorta. The alpha 1-adrenoceptor selective stimulant (-)-phenylephrine was included for comparison. All agonists induced concentration-dependent contractions in both preparations. Calcium entry blockade by D 600 almost abolished the contractions evoked by B-HT 920 and UK 14,304 in rat aorta while those evoked in guinea-pig aorta were less strongly affected. Contractions elicited by (-)-phenylephrine were moderately impaired by D 600 in rat aorta whereas there was only a limited effect in guinea-pig aorta. Analysis of the prazosin and yohimbine antagonism of B-HT 920- and UK 14,304-evoked contractions showed the involvement of alpha 1-like adrenoceptors in rat and guinea-pig aorta, prazosin being approximately 1000 times more potent that yohimbine. The results show that B-HT 920 and UK 14,304 contract rat and guinea-pig aorta via alpha 1-like adrenoceptors which are not identical. It is submitted that rat and guinea-pig alpha 1-adrenoceptors activate different contractile processes.

Guanfacine and clonidine: antihypertensive and withdrawal characteristics after continuous infusion and its interruption in the spontaneously hypertensive and normotensive rat

SummaryIn conscious unrestrained spontaneously hypertensive and normotensive rats, prepared with permanently indwelling abdominal aortic catheters, the effects on blood pressure and heart rate of a 12-day continuous subcutaneous infusion of guanfacine (10 mg/kg/day) and clonidine (500 μg/kg/day) and sudden interruption of these treatments were studied. Both drugs significantly and consistently reduced the mean arterial pressure and heart rate throughout the infusion period in the SH rats, but not in the normotensive animals. The magnitude of the effects of both drugs in the SH rat were similar. Following withdrawal of treatment with guanfacine, a discontinuation syndrome was evoked, much less severe than that observed after suspension of the infusion with clonidine. The withdrawal syndromes were characterized by an overshoot of heart rate and a period of blood pressure lability. In spite of the ineffectiveness of guanfacine and clonidine to reduce blood pressure and heart rate consistently in the normotensive rat, similar withdrawal patterns as those found in the SH rat were observed. These findings are in general agreement with the results previously found in clinical studies in hypertensive patients. The spontaneously hypertensive rat may prove a suitable animal model for pre-clinical studies of discontinuation symptoms after cessation of treatment with antihypertensive drugs.

The influence of α1- and α2-adrenoceptor agonists on cardiac output in rats and cats

In pithed rats, but not in pithed cats, the α2‐/dopamine agonist B‐HT 920 (10–300 μg kg−1) increased cardiac output. The increase was inhibited by yohimbine (1 mg kg−1), but not by sulpiride (0·3 mg kg−1) and nifedipine (1 mg kg−1). Both in pithed rats and cats, the α1−adrenoceptor agonist methoxamine (30–300 μg kg−1 and 30–1000 μg kg−1, respectively) increased cardiac output. This increase (rats) was inhibited by prazosin (0·1 mg kg−1). The results indicate the existence of functional venous α2−adrenoceptors in pithed rats, and their absence in pithed cats. Furthermore, α2−adrenoceptor−mediated venoconstriction appears independent of extracellular calcium.

Discontinuation syndrome after continuous infusion of clonidine in the spontaneously hypertensive rat

Abstract In conscious spontaneously hypertensive rats prepared with permanent indwelling aortic catheters the continuous infusion of clonidine (500 μg/kg/day) via an ALZET miniosmopump induced significant reductions in blood pressure and heart rate. These effects were well sustained during 12 days of treatment. A marked overshoot in heart rate was observed following withdrawal of clonidine administration. The tachycardia persisted for more than 36 hours. Mean arterial pressure exceeded control level slightly in the immediate withdrawal period only, whereas significant blood pressure lability was observed for more than 36 hours. These withdrawal symptoms were accompanied by an elevation of plasma noradrenaline concentration. The present study shows the consistent antihypertensive and bradycardic activities of clonidine during 12 days of infusion in spontaneously hypertensive rats. Furthermore, this model may provide a useful tool in the study of withdrawal phenomena of antihypertensive drugs.

Inhibitory effect of calcium antagonist drugs on vasoconstriction induced by vascular alpha2-adrenoceptor stimulation

A survey is given of the mechanisms of the antihypertensive effect of calcium entry blockers. The main background of the antihypertensive/hypotensive action is dilatation of precapillary arterioles (resistance vessels that cause a reduction in total peripheral resistance and, hence, a decrease in blood pressure). The vascular relaxation is caused by an inhibition of the transmembranous calcium influx and, probably less so, by interference with calmoduline. Calcium entry blockers significantly reduce the vasoconstriction induced by the excitation of vascular postsynaptic alpha 2 adrenoceptors. The inhibitory effect of calcium entry blockers is reversed by the calcium entry promoter Bay k 8644. The vasoconstriction induced by alpha 1-adrenoceptor stimulation is less generally influenced by calcium entry blockers than the alpha 2 effects. The interference with alpha 2-adrenoceptor-induced vasoconstriction may contribute to the vasodilator action of the calcium entry blockers, especially in hypertensive patients who show a hyperreactivity to pressor responses toward catecholamines.

Lack of effect of D600 on α1-adrenoceptor-mediated contractions of rat isolated anococcygeus muscle

The experiments concerned the contractile responses of rat anococcygeus muscle to the selective alpha 1-adrenoceptor agonists cirazoline, phenylephrine, methoxamine, St 587, Sgd 101/75, amidephrine and SK&F 89748-A and the effect of the calcium entry blocker D600 on the responses. The effects of noradrenaline, adrenaline, K+, tyramine and electrical field stimulation were studied as well. The potency series of the various agonists on rat anococcygeus muscle differed from the series for rat and guinea-pig aorta, indicating differences in the structure of the alpha 1-adrenoceptors on these tissues. D600 was ineffective in inhibiting contractions of rat anococcygeus muscle to the various agonists, but effectively attenuated the responses to K+ in anococcygeus muscle from rats pretreated with reserpine or in prazosin-induced preparations. These data indicate that alpha 1-adrenoceptor activation in rat anococcygeus muscle triggers contractions which do not primarily require the influx of extracellular calcium. In this respect, the smooth muscle from the rat anococcygeus muscle differs from vascular smooth muscle from this species.

Heterogeneity of the interaction between α1- and α2-adrenoceptor agonists with their respective receptors in the vascular system of the pithed rat

The subdivision of α1- and α2-adrenoceptor-mediated pressor responses to different agonists based upon the influence of β2-adrenoceptor-mediated vasodilatation was further investigated in the pithed normotensive rat. The effect of salbutamol (4.18 × 10−6 mol/kg) on the α1-adrenoceptor-mediated increase in diastolic pressure due to dopamine and amidephrine as well as on the α2-adrenoceptor-mediated pressor response to azepexole, DP-6,7-ADTN, M-7, TL-99 and dopamine was assessed. The α1-pressor responses to amidephrine and dopamine were only slightly attenuated by salbutamol. The α2-adrenoceptor-mediated increase in diastolic pressure due to B-HT 933 was strongly antagonized by salbutamol in contrast to the effect of dopamine, DP-6,7-ADTN and M-7. TL-99 occupied an intermediate position. The data do not support the existence of distinctly different subtypes of α1- and α2-adrenoceptors but favor the hypothesis that both α1- and α2- adrenoceptors are activated in a unique way by each of their respective agonists.

DIFFERENTIAL PREJUNCTIONAL EFFECT OF CAPTOPRIL AND SARALASIN ON NEUROGENIC VASOCONSTRICTION IN PITHED NORMOTENSIVE RATS

The present study describes a differential inhibitory effect of captopril and [Sar1 Ala8]angiotensin II (saralasin) on the neurogenic vasoconstriction in pithed normotensive rats. In pithed normotensive rats with intact kidneys captopril more profoundly inhibited the vasopressor response to spinal stimulation than observed for saralasin. Bilateral nephrectomy also diminished the hypertensive response to spinal stimulation. After bilateral nephrectomy, 1 h previously, captopril but not saralasin diminished the hypertensive response to spinal stimulation. After bilateral nephrectomy, 18-24 h previously, captopril did not produce an additional reduction of the vasopressor response to spinal stimulation. In contrast, saralasin significantly potentiated the neurogenic vasoconstriction. The results suggest that both captopril and saralasin diminish the hypertensive response to spinal stimulation by producing dilatation of vascular smooth muscle in pithed normotensive rats. Apart from this common mechanism, a differential effect of captopril and saralasin on the neurogenic vasoconstriction can be observed. In contrast to saralasin, captopril may depress the neurogenic vasoconstriction in pithed normotensive rats by blocking the sympathofacilitatory action induced by subpressor levels of angiotensin II (AII). In pithed normotensive rats, saralasin may mimic the sympathofacilitatory action of subpressor AII.