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It is rather the rate of the vasodilator effect than its magnitude which determines the triggering of reflex tachycardia associated with dihydropyridine calcium antagonists (DHP-CA). We therefore compared the rate of the vasodilator effects of a series of CA (both DHP and non-DHP) in rat isolated mesenteric artery preparations (size 256 +/- 3 microns, length 2 mm) from male Wistar rats (weighing 300-350 g) in an isolated wire myograph according to Mulvany and Halpern [12]. The mean force of the KCl-induced contraction amounted to 2.3 +/- 0.1 mN/mm. Potency (given as IC50-values), differential time course of action and recovery of the contractile response of the vessels after wash-out were established. These three parameters adhere to the following sequences: (1. potency) barnidipine [corrected] > (S)-lercanidipine > barnidipine racemate [corrected]> amlodipine > nifedipine, lacidipine > (R)-lercanidipine > verapamil, mibefradil; (2. differential time course) lacidipine, amlodipine > (S)- and (R)-lercanidipine, barnidipine [corrected], barnidipine racemate [corrected] > mibefradil, verapamil, nifedipine; (3. recovery) nifedipine > verapamil, barnidipine [corrected], amlodipine > barnidipine, lacidipine > mibefradil, (R)-lercanidipine > (S)-lercanidipine. In conclusion, barnidipine [corrected] proved to be the most potent vasodilator agent; interestingly, barnidipine was 20 times less potent when applied as a racemic mixture. A slow onset of action in DHP is a very important mechanism in preventing reflex tachycardia. For non-DHP (verapamil, mibefradil) reflex tachycardia probably is prevented by a direct effect on the conductive tissue in the myocardium.

The influence of various vasodilator and constrictor drugs was studied in isolated mesenteric arteries obtained from obese and lean Zucker rats. The obese Zucker rats were moderately hypertensive and their isolated small arteries were not hypertrophied. All vasoconstrictor agents studied (noradrenaline, methoxamine, serotonin, calcium chloride, potassium chloride) caused the same effects in isolated arteries taken from obese and lean (control) Zucker rats; respectively. In vessels from obese Zucker rats, the vasodilator responses to sodium nitroprusside, methacholine, the K(+)-channel opener cromakalim and nifedipine were the same as in control preparations. In conclusion, isolated mesenteric arteries from obese Zucker rats do not show relevant structural changes, and the pharmacodynamic behaviour of such vessels appears to be the same as that of control preparations. Neither the diabetic hyperinsulinaemic state not the hyperlipoproteinaemia in the obese Zucker rats appear to cause serious vascular damage.