Selective antagonism of humoral versus neural vasoconstrictor responses by nisoldipine.

Abstract

SUMMARY The effects of nisoldipine administration on vascular reactivity to humoral and neural vasoconstrictor stimuli were examined in the intact rat. For these experiments, rats were instrumented with miniaturized pulsed Doppler flow probes to allow continuous measurement of renal, mesenteric, and hindquarters blood flow. In conscious and anesthetized rats, intravenous doses of angiotensin II (75 and 150 ng/kg), norepinephrine (0.6 and 1.2 /xg/kg), and epinephrine (0.6 and 1.2 /zg/kg) caused dose-dependent increases in arterial pressure and renal and mesenteric vascular resistance. Nisoldipine (0.7 /xg/min) administration significantly attentuated (p < 0.05) the pressor and regional vasoconstrictor actions of all three circulating pressor agents; however, nisoldipine infusion had little effect on neurally mediated regional vasoconstrictor responses elicited by electrical stimulation of the posterior hypothalamus or greater splanchnic nerve. These data indicate that nisoldipine depressed vascular responsiveness to humoral vasoconstrictor agents, while neural vasoconstrictor responses were unaffected. Thus nisoldipine appears to exert preferential antagonistic effects on humoral rather than on neural vasoconstrictor stimuli. (Hypertension 7: 216-222, 1985) KEY WORDS • calcium entry blockers • norepinephrine • epinephrine • angiotensin II neural vasoconstriction • vascular reactivity • regional vascular resistance T HE second-generation dihydropyridine calcium entry blocker (CEB) nisoldipine 1 has been demonstrated to lower arterial pressure by reducing total peripheral resistance in experimental animals 2 " 5 and hypertensive patients. Several investigators have suggested that, in addition to direct smooth muscle relaxation, 2 6 7 nisoldipine may lower arterial pressure, in part, by noncompetitively antagonizing aadrenergic receptor vasoconstrictor responses. Nisoldipine and other CEBs have been reported to selectively antagonize ctj-adrenergic receptor mediated vasoconstriction in isolated smooth muscle 6 -8 and in pithed rats and cats.9 "" These effects may depend on the specific tissue or animal species being studied, however; other investigators have reported that CEBs attenuate both a,-and a 2 -adrenergic vasoconstriction. Supported by grants HLB-14388 and HLB-07121 from the National Heart, Lung and Blood Institute, National Institutes of Health, and a gift from the Searle Family Trust.Address for reprints: Dr. Michael J. Brody, Department of Pharmacology, University of Iowa College of Medicine, Iowa City, Iowa 52242.Received March 12, 1983; revision accepted September 19, 1984. receptor responses, CEBs appear to inhibit angiotensin II (ANG II) vasoconstrictor responses in the isolated perfused hindquarters of the dog 16 and the pithed rat. 17The effects of CEBs on vascular reactivity to pressor stimuli in intact animals, however, are relatively unknown.In a previous study in our laboratory, 4 using a pulsed Doppler flowmeter to monitor regional blood flow, we described the effects of nisoldipine on ...

Effect of Nisoldipine on De-Endothelialized Large Coronary Artery in Isolated Working Rabbit Hearts

“…2). It has been previously shown that calcium antago nists abolish the vasoconstrictor responses to histamine and to a variety of vasoactive agents such as serotonin and catecholamines [1,25,26]. Our findings are in agreement with those of Perez et al [10], who found that in open chest dogs, intravenous infusion of nisoldipine abolished the vasoconstriction of large coronary arteries induced by topical application of potassium ion; Drexler et al [9] also reported that intravenous infusion of nisoldipine in rats induced a significant va sodilatation of coronary arteries during rest and exercise.…”

Characteristics of pressor response to endothelin in spontaneously hypertensive and Wistar-Kyoto rats.

“…It has been shown, however, that Ca 2+ channel blockers attenuate the pressor and regional vasoconstrictor actions of Ang II and norepinephrine. 22 A bolus injection of nicardipine 0.1 mg/kg lowered the blood pressure (see Figure 3, legend) and also partly suppressed the pressor actions of Ang II and norepinephrine (data not shown). However, the result that the rapid pressor response to ET is relatively resistant to nicardipine favors the possibility that the inhibition of the slow pressor response to ET is due to a specific suppressing action of nicardipine.…”

Calcium Antagonists and Sympathetic Neuroeffector Function

“…No attempt was made to Identify the aadrenoreceptor subtype involved in the vasoconstrictor actions of noradrenaline and adrenaline. However, these results demonstrate that an influx of extracellular Ca2+ was necessary for the vasoconstrictor actions of these compounds (Lappe et al, 1985). A recent study in humans has also shown that pressor responses to aI-(phenylephrine) as well as (~2 -(amethylnoradrenalhe)-adrenoreceptor s h ulation were inhibited after four days of oral treatment with calcium antagonists (Pasanisi, Elliott, Meredith, Sumner 81 Reid, 1985).…”