Characterization of calcium channel blocker induced smooth muscle relaxation using a model of isolated corpus cavernosum.
Several classes of smooth muscle relaxing agents have proven effective in relaxing cavernosal smooth muscle and useful in the pharmacotherapy of erectile dysfunction. The purpose of this investigation was to determine whether the calcium channel blockers (CCB) relax cavernosal smooth muscle. Thirty-two rabbit cavernosal strips were contracted by electrical field stimulation, and contraction inhibition was tested in response to cumulative doses (10(-8) M. to 10(-4) M.) of verapamil (V), diltiazem (D), isradipine (I), nicardipine (Nc) and nifedipine (Nf). All of the calcium channel blockers were effective at inhibiting electrically induced contractions (p < 0.0001 when CCB was compared with control; p < 0.05 when V or D was compared with I, Nc or Nf). Sixteen cavernosal strips were precontracted with 10(-5) M. norepinephrine. Relaxation in response to cumulative doses of each CCB was determined. Verapamil and the dihydropyridines (isradipine, nicardipine and nifedipine), but not diltiazem, were effective at relaxing norepinephrine induced contractions at 10(-5) and 10(-4) M. with verapamil most effective at 10(-4) M. concentration (p < 0.0001 by ANOVA at both concentrations when V, I, Nc, or Nf was compared with control). Sixteen cavernosal strips were incubated in solutions of 10(-5) and 10(-4) M. of each CCB followed by cumulative addition of norepinephrine (concentration range 10(-8) to 10(-4) M.). Preincubation with CCB did not affect the concentration of norepinephrine at which 50% of maximal cavernosal contractile response occurred (ED50). Maximum active tension of norepinephrine induced contractions was moderately decreased after CCB preincubation with 10(-4) M. of each dihydropyridine. It is concluded that the calcium channel blockers are effective in relaxing cavernosal smooth muscle and therefore possess potential as intracavernous pharmacotherapeutic agents for the treatment of erectile dysfunction. Verapamil appears to be the best candidate for further testing and clinical trial.
Kerfoot
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Division of Urology, Duke University Medical Center, Durham, North Carolina 27710.
Park
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Schwartz
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Hagen
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Carson
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D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D010413:Penis / Q000502:physiology*; D011817:Rabbits; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D014700:Verapamil; D004110:Diltiazem; D009638:Norepinephrine